Interventional, Randomized, Double-blind, Parallel-group, Placebo-controlled Study of Lu AG09222 for the Prevention of Migraine in Patients With Unsuccessful Prior Preventive Treatments
Phase: PHASE2
Conditions: Migraine
Sponsor: H. Lundbeck A/S

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Clinical Study Protocol
Interventional, randomized, double-blind, parallel-group, 
placebo-controlled study of Lu AG09222 for the prevention of 
migraine in patients with unsuccessful prior preventive 
treatments
Lu AG09222
Study No.:
19678A
EudraCT/IND No.:
2020-005924-12 (EU) / 154836 (US)
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
3.0 (includes all Clinical Study Protocol changes since Edition 2.0)
(the version No. in the footer is the system version No.)
Date of edition:
11 July 2022
Edition history:
Edition 2.0 (submitted protocol), 24 January 2022
Edition 1.0 (original submitted protocol), 28 May 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.
NCT05133323

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∀Intercurrent events:  The IEs are defined above.  Use of acute rescue medication or preventive migraine 
therapy (different from investigational medication) is taken into account using a composite strategy.  
Incorrect administration of treatment is handled using a treatment policy strategy.  The IE “use of 
preventive migraine therapy” will be addressed with a hypothetical strategy. If withdrawal from study 
occurred, data obtained after withdrawal will be included in the analysis, and, if IEs occur after withdrawal 
from study (use of acute rescue medication or preventive migraine therapy), the methods described for 
handling IEs will be applied. Full details of the statistical methods for handling IEs and missing data, will 
be described in the SAP.
∀Population level summary (primary analysis):  The least-squares mean difference in change from baseline in 
the number of MMDs (Weeks 1 to 4)  between the high dose of 
 and placebo, based on an analysis 
of covariance (ANCOVA) with baseline MMDs as covariate and treatment (placebo, low dose, high dose), 
population (EM or CM), and an interaction between the stratification factors (region and 
 
! Sensitivity analyses of the primary endpoint:
∀The impact of the imputation of the primary endpoint will be assessed in a sensitivity analysis, applying 
different measures of imputation.  For patients experiencing an IE, the imputation strategy will depend on 
the type of IE.
∀The primary analysis model will be applied, including an adjustment for whether or not a patient had a 
COVID-19 vaccination during the 4 weeks following IMP administration.
Testing Strategy
The type 1 error will only be controlled for the primary analysis comparing the primary endpoint (change from 
baseline in MMDs [Weeks 1 to 4]) for the high dose of Lu AG09222 to placebo at a one-sided 5% significance
level.  Other analyses will be considered exploratory, and statistical significance will be considered indicative, 
rather than confirmative, for the finding.
Sample Size Considerations
Simulations were used to determine a sample size that ensured at least 80% power at a one-sided 5% 
significance level for detecting an effect of 2.1 on the 
 dose when using an ANCOVA with baseline 
MMD as a covariate and treatment and population (EM or CM) as fixed factors.  A population with 30% EM 
and 70% CM patients was assumed with standard deviations of 3.8 and 6.1, respectively, which resulted in a 
standard deviation of 5.6 for the full population.  The resulting required sample size is 86 patients per arm for 
the 
 dose and placebo.  No formal power calculation was performed for the 
dose.  A sample size 
of 43 patients per arm was considered sufficient to evaluate the relevant endpoints for this dose, which results in 
a randomization ratio of 2:1:2.  Adjusting for an expected 5% dropout rate, a total sample size of 230 will be 
required.
The cap of 30% for the EM population results in a similar precision (standard error) for the treatment estimates 
for the EM and CM populations.
Simulations are based on 10000 runs.
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Panel 2
Study Procedures and Assessments
Visit Name
Screening
Baseline + IMP
Primary Outcome
Safety Follow-up 
Withdrawalc
Efficacy Follow-up 
(telephone contact)c
Visit Number
1
SCR
2
BL
3
4
PO
5
6
SFU
WD
EFU
Type of Visitx
Clinic Clinic
Clinic
/Tele
visit/
Home
Clinic
/Tele
visit/
Home
Clinic
/Tele
visit/
Home
Clinic
Clinic
/Tele
visit/ 
Home
Telep
hone
Day/End of Weeka
-4
0
2
4
8
12
4
Visit Windowb (days relative to nominal visit)
-2
#2
#2
#2
#5
#2
Screening and Baseline Procedures and Assessments
Signed informed consent form
∃
Separate informed consent forms (optional)
∃
Demographics (age, sex, race)
∃
Diagnosis
∃
Disease-specific historyd
∃
Relevant history (social, medical, psychiatric, 
neurological)
∃
Documented evidence of previous failure of 2-4 
migraine preventive medicationse
∃
Recent medication (prescription and 
non-prescription), herbal remedies, 
non-pharmacological interventions, vitamin and 
mineral supplements
∃
Height 
∃
Blood sampling for serology (HBsAg, anti-HBs, 
anti-HBc, and anti-HCV)
∃
Blood sampling for other screening (e.g., β-hCG, 
FSH)
∃
Urine drug screen and alcohol screen
∃
Inclusion/exclusion criteria
∃
∃
Signs and symptoms present at Screening and 
Baseline (before IMP administration) (recorded on 
an Adverse Event Form)
∃
∃
 
∃j
Randomization
∃
Efficacy Assessments
eDiary daily recordingf,g
∃
∃j
∃
∃
∃
∃c,k
∃k
∃k
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Table of Contents
List of Panels........................................................................................................................... 23
List of Abbreviations and Definitions of Terms..................................................................... 24
Major Changes Since Last Edition......................................................................................... 27
1
Introduction.................................................................................................................... 28
1.1
Background........................................................................................................... 28
1.1.1
Overview ............................................................................................... 28
1.1.2
Nonclinical Data .................................................................................... 29
1.1.2.1
Primary Pharmacology ........................................................... 29
1.1.2.2
Safety Pharmacology.............................................................. 30
1.1.2.3
Pharmacokinetics and Metabolism.......................................... 30
1.1.2.4
Toxicology............................................................................. 30
1.1.3
Clinical Data.......................................................................................... 31
1.2
Rationale for the Study.......................................................................................... 32
2
Objectives and Endpoints............................................................................................... 33
3
Study Design................................................................................................................... 36
3.1
Overview of the Study Design............................................................................... 36
3.2
Rationale for the Study Design.............................................................................. 38
4
Ethics .............................................................................................................................. 40
4.1
Ethical Rationale................................................................................................... 40
4.2
Informed Consent.................................................................................................. 41
4.3
Personal Data Protection ....................................................................................... 42
4.4
Ethics Committee(s) and Institutional Review Board(s)......................................... 43
5
Study Population ............................................................................................................ 43
5.1
Number of Patients and Countries ......................................................................... 43
5.2
Patient Recruitment............................................................................................... 43
5.3
Selection Criteria .................................................................................................. 43
5.4
Withdrawal Criteria............................................................................................... 48
6
Investigational Medicinal Products................................................................................ 48
6.1
Treatment Regimen............................................................................................... 48
6.2
IMP, Formulation and Strength ............................................................................. 48
6.3
Manufacturing, Packaging, Labelling, and Storage of IMP(s) ................................ 49
6.4
Method of Assigning Patients to Treatment ........................................................... 50
6.5
IMP Accountability............................................................................................... 50
6.6
Unblinding Procedures.......................................................................................... 50
6.7
Post-study Access to IMP(s).................................................................................. 50
7
Concomitant Medication................................................................................................ 51
8
Study Visit Plan.............................................................................................................. 51
8.1
Overview .............................................................................................................. 51
8.2
Screening Visit (Visit 1)........................................................................................ 52
8.2.1
Pre-screening ......................................................................................... 53
8.2.2
Patient Identification Card...................................................................... 53
8.2.3
Re-screening .......................................................................................... 53

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16.8.6
Analysis of the Exploratory Endpoints.................................................... 93
16.8.7
Analysis of Subgroups............................................................................ 94
16.9
Safety Analyses..................................................................................................... 94
16.9.1
Analysis of Adverse Events.................................................................... 94
16.9.2
Analysis of Other Safety Endpoints........................................................ 95
16.10 Sample Size and Power......................................................................................... 95
16.11 Statistical Analysis Plan ........................................................................................ 95
17
Clinical Study Report and Publications......................................................................... 96
17.1
Data Ownership .................................................................................................... 96
17.2
Clinical Study Report............................................................................................ 96
17.3
Summary of Clinical Study Results ....................................................................... 96
17.4
Publications .......................................................................................................... 96
18
Indemnity and Insurance ............................................................................................... 96
19
Finance............................................................................................................................ 96
19.1
Site Agreements.................................................................................................... 96
19.2
Financial Disclosure.............................................................................................. 97
19.3
Equipment............................................................................................................. 97
References ............................................................................................................................... 98

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Appendices
Appendix I
Clinical Study Protocol Authentication and Authorization............................ 102
Appendix II
Recent and Concomitant Medication Disallowed or Allowed with Restrictions
.................................................................................................................... 104
Appendix III
Interpretation of Hepatitis B Serologic Test Results ..................................... 108

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List of Panels
Panel 1
Study Design.........................................................................................................12
Panel 2
Study Procedures and Assessments........................................................................13
Panel 3
Objectives and Endpoints......................................................................................33
Panel 4
ICHD-3 Guidelines for Migraine...........................................................................62
Panel 5
Clinical Safety Laboratory Tests............................................................................71

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List of Abbreviations and Definitions of Terms
ADA
anti-drug antibodies
ANCOVA
analysis of covariance
anti-HCV
hepatitis C virus antibody
anti-HBc
hepatitis B core antibody
anti-HBs
hepatitis B surface antibody
APRS
all patients randomized set
APTS
all patients treated set
%-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BSC
best supportive care
CGRP
calcitonin gene-related peptide
CI
confidence interval
ClinRO
clinician-reported outcome
CM
chronic migraine
Cmax
maximum observed concentration
CNS
central nervous system
COA
clinical outcome assessment
CRA
clinical research associate
CRO
contract research organization
CRP
C-reactive protein
C-SSRS
Columbia-Suicide Severity Rating Scale 
DBL
database lock
DMC
Data Monitoring Committee
DSM-5®
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
EM
episodic migraine
EOI
end of infusion
EudraCT
European Union Drug Regulating Authorities Clinical Trials
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FAS
full analysis set
FAS-LT
full analysis set long term
FIH
first-in-human 
FSH
follicle-stimulating hormone
HBsAg
hepatitis B surface antigen
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICHD-3
International Classification of Headache Disorders Third Edition
ICMJE
International Committee of Medical Journal Editors
IE
intercurrent event
IHS
International Headache Society
IMP
investigational medicinal product
IRB
institutional review board
IRR
infusion-related reaction
IRT
interactive response technology
IV
intravenous(ly)
Lu
Lundbeck
MHD
monthly headache day
MMD
monthly migraine day
MMRM
mixed model for repeated measurements
MOH
medication overuse headache
NAb
neutralizing antibodies
PCR
polymerase chain reaction
PD
Pharmacodynamic(s)
PK
pharmacokinetic(s)
PoC
proof-of-concept
popPK
population pharmacokinetic(s)
PR
specific ECG interval describing atrioventricular conduction
PRO
patient-reported outcome
QP
qualified person
QRS
specific ECG interval describing ventricular depolarization
QT
specific ECG interval describing ventricular depolarization/repolarization
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QTc
heart rate-corrected QT interval
RR
specific ECG interval describing the ventricular depolarization/repolarization cycle
SAE
serious adverse event
SAP
Statistical Analysis Plan
SC
subcutaneous(ly)
SPG
sphenopalatine ganglion
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TMF
trial master file
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Major Changes Since Last Edition
All descriptions of and references to the non-binding interim analysis for futility are removed 
across the Clinical Study Protocol, as the interim analysis for futility will not be conducted as 
informed to sites as per memo 19678A Interim Analysis for Futility (dated 20-06-2022).
Minor wording clarifications/edits are also made in particular in Appendix II: Recent and 
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1
Introduction
1.1
Background
1.1.1
Overview
Migraine is a disabling disorder characterized by moderate-severe headache which is 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.  
Migraine is more common in women and most prevalent through the third and fourth decades 
of life, amplifying its impact on family and career development.2  Migraine is one of the most 
prevalent neurological diseases for which medical treatment is sought and worldwide is 
considered the leading cause of disability for people under the age of 50.3,4
Generally, migraine begins as an episodic disease.  Between attacks of migraine, the nervous 
system returns to a normal (premorbid) state of function.  However, among patients with 
episodic migraine (EM), approximately 2.5% per year progress to chronic migraine (CM), 
that is, headache on 15 days or more a month of which 8 are migraine attacks, for at least 
3 consecutive months.1,5,6  In CM, headaches are more frequent and migraine-related life 
impact and disability are much greater than those observed in EM.  In addition, CM has a 
stronger association with co-morbid conditions such as anxiety, depression, and non-headache 
pain.
Currently, pharmacological treatments of migraine include acute and preventive treatments. 
Preventive treatments are used on a sustained basis for periods of months to years to prevent 
migraine from occurring. Preventive treatment may be appropriate in a number of instances, 
including where frequency of attacks per month is 2 or higher or where a patient’s quality of 
life is severely impaired.7  Conventional preventive treatments belong to different 
pharmacological categories (e.g., 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.2,8,9,10,11,12,13 Furthermore, preventive treatment can take weeks to months to achieve 
optimal efficacy.14,15  Thus, there is a need for preventive medications that are more effective 
and better tolerated than the current standard of care.16  The high prevalence of migraine and 
its associated disability, especially when transformed to CM, are important justifications for 
developing effective treatments for the prevention of migraine.  Establishing a robust and 
clinically meaningful migraine preventive effect as early as possible is a particularly 
important outcome for patients and is important for facilitating management and health 
resource decisions by healthcare professionals.  This is highlighted in the recently published 
guidelines of the International Headache Society (IHS) for controlled studies of preventive 
treatment of EM and CM in adults where the onset of preventive treatment effect is 
recommended as a secondary endpoint.17,18
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a multifunctional neuropeptide 
that is implicated in migraine pathophysiology.19,20,21,22,23 PACAP is expressed, along with its 
receptors, throughout the nervous system, including distinct areas suggestive of a role in 

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migraine pathophysiology such as the trigeminovascular system, trigeminal ganglia, 
trigeminal nucleus caudalis, dorsal horn of the spinal cord, brainstem, hypothalamus, 
pituitary, and the otic and sphenopalatine ganglions (SPGs).24,25,26,27,28,29 PACAP exists in 
two forms, one composed of 38 amino acids (PACAP38) and another composed of 27 amino 
acids (PACAP27). Of the two forms, PACAP38 is the more prevalent, representing up to 90% 
of PACAP forms in mammalian tissues.20
A mechanistic role for PACAP38 in migraine is supported by several clinical observations: 
(1) an infusion of PACAP38 in patients with migraine without aura triggers migraine-like 
attacks (associated with photophobia, phonophobia, and nausea) and sustained vasodilation of 
extracranial arteries;21,30,31 (2) PACAP38-induced migraine-like attacks respond to 
triptans;32,33 (3) plasma concentrations of PACAP38 are elevated during spontaneous
migraine attacks (ictal), as compared to inter-ictal levels;33 and (4) in patients with migraine 
headache, plasma PACAP38 levels decrease after sumatriptan treatment correlating with 
headache amelioration.34
PACAP differs from calcitonin gene-related peptide (GCRP) in that it has greater SPG and 
parasympathetic involvement.35  The SPG is considered to play a role in headache pain and 
cranial autonomic symptoms caused by activation of the trigeminal-autonomic reflex, which 
might entail the involvement of PACAP in the development of cranial autonomic symptoms. 
Moreover, chronic stress and pain paradigms upregulate the PACAP signalling axis, 
suggesting that PACAP may play a critical role in central neurocircuits that mediate pain and 
stress response behaviours.36,37,38,39  Finally, PACAP acts as a mast cell degranulator with the 
ability to impact neurogenic inflammatory processes and central pain signalling and 
sensitization.40,41
Lu AG09222 is a humanized monoclonal antibody that inhibits the action of PACAP and is 
being developed by H. Lundbeck A/S for the treatment of conditions that may benefit from 
the inhibition of PACAP, including migraine.  Lu AG09222 binds with high affinity to both 
PACAP38 and PACAP27, thus blocking signalling through the PACAP receptors (PAC1-R, 
VPAC1-R, and VPAC2-R) and inhibits endogenously released PACAP in vivo.  Considering 
the clinical observations that support a mechanistic role for PACAP in migraine and the 
ability of Lu AG09222 to inhibit PACAP, Lu AG09222 may potentially provide efficacy in 
migraine populations based on a mechanism of action that differs from currently available 
preventive treatments for migraine.
The following sections provide a brief overview of the nonclinical and clinical data currently 
available for Lu AG09222.  Refer to the current version of the Investigator’s Brochure for
further details.42
1.1.2
Nonclinical Data
1.1.2.1
Primary Pharmacology
PACAP and its receptors are expressed in multiple peripheral organs, as well as in the 
peripheral and central the nervous system.43,44,45,46  Upon PACAP receptor binding, the 
receptors VPAC1-R, VPAC2-R, and PAC1-R all have the ability to cause intracellular 

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There is a theoretical potential for Lu AG09222 to modulate inflammatory processes and 
thereby exacerbate immune complex-driven pathology, which should be considered during 
clinical administration.
Results from the nonclinical safety studies suggest that the risk associated with the 
administration of Lu AG09222 is low and support multiple-dose clinical administration with 
Lu AG09222 IV or SC.
1.1.3
Clinical Data
Lu AG09222 has been studied in the first-in-human (FIH) study (18902A) which is currently 
in the reporting phase. Thus, the data are preliminary and based on a cut-off date of 
24 September 2020, corresponding to the database lock (DBL). This was a randomized, 
double-blind, placebo-controlled, single ascending dose Phase I study to determine the safety, 
tolerability, and PK of Lu AG09222. The study included healthy men and women aged 18 to 
55 years and comprised two parts:  a dose-escalating part (Part A) and an expanded-cohort 
part to assess the combination treatment of Lu AG09222 and sumatriptan (Part B).  In Part A, 
8 healthy men per cohort (Cohorts 1 to 7) were randomized (3:1) to Lu AG09222 IV in single 
ascending doses of 
 and 
 or placebo.  Additionally, 8 healthy 
women (Cohort 8) were randomized (3:1) to Lu AG09222 IV to 
or placebo. In 
Part B, 8 healthy men and 8 healthy women were randomized (1:1) in Cohort 9 to 
Lu AG09222 
 IV (dose determined based on Part A) or placebo, both treatments in 
combination with sumatriptan 6 mg SC administered 2 hours after the end of the IV infusion.  
In Cohort 10, 8 healthy men and 8 healthy women were randomized (3:1) to Lu AG09222 
 SC or placebo.
Preliminary safety data from the FIH study indicate that administration of Lu AG09222 in 
single doses of 
and 
 in healthy subjects is generally safe and 
well tolerated.  A total of 96 healthy subjects received placebo, Lu AG09222 IV or SC, 
Lu AG09222 IV plus sumatriptan SC, or placebo plus sumatriptan SC.
Of the 60 subjects treated with Lu AG0922 IV or SC, 32 had a total of 65 non-serious 
treatment-emergent adverse events (TEAEs), while 8 of 8 subjects treated with Lu AG09222 
plus sumatriptan had a total of 17 TEAEs.  No subjects died or withdrew due to adverse 
events during the study.
One serious adverse event (SAE) of Grade 2 [moderate] chilblains (perniosis) was reported.  
The first lesions were noted at approximately 5 half-lives after administration of Lu AG09222 
 IV plus sumatriptan 6 mg SC. The SAE was considered related to Lu AG09222 and 
not related to sumatriptan by the investigator. The investigator considered cold exposure 
leading to abnormal vascular and nerve function in the extremities as a mechanism underlying
the chilblains. Lundbeck considered the event possibly related to Lu AG09222 and 
considered the primary cause for this event to be cold exposure in a subject with a possible 
bug bite and a history of psoriasis, although a potential contribution of Lu AG09222 could not 
be excluded. The subject tested negative for ADA. The most common adverse events seen in 
more than 2 subjects were upper respiratory tract infection, headache, diarrhoea, liver function 
test abnormal, dizziness, dysmenorrhoea, and presyncope.
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Most adverse events were mild.  There was no pattern in the distribution of TEAEs across the 
doses of Lu AG0922 to indicate a causal relationship between the TEAEs and Lu AG09222.  
There were no clinically significant findings or trends in clinical safety laboratory tests, vital 
signs, QT intervals, or physical or eye examinations.
Of the 68 subjects who received Lu AG09222, 8 subjects were ADA-positive during the 
study, with no positive ADA tests observed before Day 84 after IMP administration 
(corresponding to approximately 
 Lu AG09222).  Of those, only one 
subject was positive for ADAs at the 6-month follow up.  All ADA-positive results were 
NAb-negative during the study, except at the 3-month follow-up, where 2 subjects were 
Nab-positive. None of the ADA-positive subjects had TEAEs associated with 
immunogenicity. 
In the preliminary PK analyses, the increase in Lu AG09222 exposure appeared to be dose
proportional over the full dose range and the half-life of Lu AG09222 was approximately 
Exposure, area under the plasma/serum concentration-time curve from time zero to infinity 
(AUC0-inf) and Cmax, for the highest dose administered, 
 IV, was below the 
no-observed-adverse-effect-level in rats and monkeys following multiple weekly 
IV administration for 4 weeks. No relevant sex differences in the PK parameters were 
observed.  The PK of Lu AG09222 
 IV were not affected following co-administration 
with sumatriptan 6 mg SC compared to the results for Lu AG09222 
IV administered 
alone.  Similarly, the PK of sumatriptan overall was not affected by the co-administration of 
Lu AG09222.
In conclusion, the preliminary safety data from this study indicate that the administration of 
Lu AG09222 in single IV doses of up to 
 in healthy subjects is generally safe and well 
tolerated.  However, although this study investigated a broad range of doses, this was only as 
single doses and only in a limited number of subjects.  Therefore, based on the profile of 
TEAEs in this study, adverse events related to the mechanism of action of Lu AG09222 may 
be expected, but the relationship between Lu AG09222 dose and the incidence of these events 
is uncertain.
1.2
Rationale for the Study
The rationale for this study is based on the observed nonclinical and clinical data of 
Lu AG09222 suggesting its potential as a safe and well-tolerated treatment to prevent 
migraine through blockade of PACAP signalling.  Preliminary results from the FIH study 
support that administration of Lu AG09222 in single IV dose of up to 
 is safe and 
generally well tolerated in healthy men and women.  The current Phase IIa study is designed 
to test proof-of-concept (PoC), that is, to investigate whether the inhibitory action of 
Lu AG09222 on the PACAP pathway can be an effective means of migraine prevention in 
patients with EM or CM.  Further, dedicated dose-finding exploration is planned if efficacy is 
observed in this study.
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Objectives
Endpoints
Safety Objective
! To evaluate the safety and tolerability of 
Lu AG09222
Safety Endpoints
! Adverse events
! Physical examination
! Absolute values and changes from baseline in clinical safety 
laboratory test values, vital signs (blood pressure, pulse rate,
respiratory rate, and body temperature), weight, and ECGs
! Potentially clinically significant clinical safety laboratory test 
values, vital signs, weight changes, and ECG parameter values
! Development of specific ADA including NAb 
! C-SSRS score 
3
Study Design
3.1
Overview of the Study Design
This study has been designed in accordance with the Declaration of Helsinki.49
This is an interventional, multi-national, multi-site, randomized, double-blind, parallel-group, 
placebo-controlled Phase IIa study designed to demonstrate PoC, that is, to investigate 
whether the inhibitory action of Lu AG09222 on the PACAP pathway can be an effective 
mechanism for migraine prevention.
This study will be conducted in compliance with the protocol, Good Clinical Practice,50 and 
applicable regulatory requirements.
An overview of the study is presented in Panel 1.
A total of 230 patients, recruited from specialist settings, are planned for randomization:  
92 in the Lu AG09222 
 group, 46 in the Lu AG09222 
 group, and 92 in the 
placebo group.
The target population for this study is defined as patients diagnosed with migraine as outlined 
in the ICHD-3 guidelines1, with documented evidence of migraine occurring on 
 per 
month prior to screening, as confirmed via prospectively collected information in the eDiary 
during the screening period and with documented evidence of failure of 2 to 4 different 
preventive migraine medications in the past 10 years.  Patients with a concurrent diagnosis of 
MOH are allowed in the study.  The aim is that approximately 30% of the randomized 
patients will have EM (patients with headache occurring on <15 days).  This will be ensured 
through a cap on the number of randomized EM patients.
Once the cap (approximately 30% of the randomized patients with EM) is reached, there will 
be a hard stop for screening further patients with a diagnosis of EM such that:
!
If the patient has a confirmed diagnosis of EM at the Screening Visit, then the patient 
should be considered as screen failed.
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Based on the data from nonclinical and clinical studies, and in combination with the 
cautionary measures implemented in the study design, the risks for the patients are considered 
well controlled and balanced with the potential benefits of the treatment.
4.2
Informed Consent
No study-related procedures, including any screening procedures, may be performed before 
the investigator has obtained written informed consent from the patient.
The signed Informed Consent Form must be obtained prior to the Screening Visit if the 
investigator/designee needs to obtain relevant documentation from the patient’s treating 
physician (i.e., patient’s general medical and migraine history, migraine treatment history 
including preventive treatment failures, recent and current medication). After the information 
has been obtained, the patient will be invited to the site again to complete the Screening Visit.
It is the responsibility of the investigator or person designated by the investigator to obtain 
written informed consent from the patient.  If the informed consent process may be delegated, 
the requirements for the delegates must be documented prior to the start of the study.  
National laws must always be adhered to when allowing potential delegation.  Any delegation 
must be documented in the site delegation log.
The investigator must identify vulnerable patients, that is, patients whose willingness to 
participate in this study might be unduly influenced by the expectation, regardless of whether 
it is justified, of benefits associated with participation, or of a retaliatory response from senior 
members of a hierarchy in case of refusal to participate.  Patients thus identified must be 
excluded from participation in the study.
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 study has been reported, about 
which treatment they received

of their right to receive information about the study results from the investigator on the 
patients’ own initiative; the results will be available approximately 1 year after the end of 
the study
The patients must be informed that persons authorized by Lundbeck and authorized personnel 
from certain authorities (domestic, foreign, data protection agencies, ethics committees [ECs],
or institutional review boards [IRBs]) may view their medical records.  The patients must also 

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4.4
Ethics Committee(s) and Institutional Review Board(s) 
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.
If applicable, interim reports on the study and reviews of its progress will be submitted to the 
EC or IRB by the investigator at intervals stipulated in its guidelines.
5
Study Population
5.1
Number of Patients and Countries
Planned regions: Approximately 30 sites in select countries across North America and
Europe.
Planned number of screened patients (approximately):
460
Planned number of randomized patients:
230
5.2
Patient Recruitment
Competitive patient recruitment between countries and sites will be used during the entire 
recruitment period to ensure that the required number of patients are randomized within the 
planned recruitment period.
The investigators will be notified immediately when the recruitment period comes to an end.
5.3
Selection Criteria
Patient selection is based on the inclusion and exclusion criteria listed below.
Patients who meet each of the inclusion criteria at the Screening Visit (unless otherwise 
specified) and none of the exclusion criteria at the Screening Visit (unless otherwise 
specified) are eligible to participate in this study.

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14. The patient, if a woman, must:
remain sexually abstinent, when this is in line with her preferred and usual lifestyle 
OR
engage exclusively in same-sex relationships
OR

agree to avoid becoming pregnant from the screening visit until 6 months after the 
administration of IMP, AND

use a highly effective contraceptive method (defined as those that result in a low 
failure rate [that is, <1% per year] when used consistently and correctly) as required 
by local regulation or practice if she is of childbearing potential and she has a male
partner. The contraceptive method must be used from the Visit 1 until 6 months after 
the administration of IMP and must include one of the following: intrauterine device; 
contraception implant; progesterone-only pills; injectable progestogen (Depo-
Provera®); combination hormonal contraceptive method (tablets, patches, or vaginal 
ring with both oestrogen and progestogen), OR

have had her last natural menstruation ≥12 months prior to the screening visit 
(confirmed by FSH level), OR
have had a hysterectomy prior to the screening visit, OR
have been surgically sterilized prior to the screening visit, OR

have a male partner who was surgically sterilized prior to the screening visit
AND

not donate ova until 6 months after the administration of IMP
15. The patient, if a man, must:
remain sexually abstinent, when this is in line with his preferred and usual lifestyle, 
OR
engage exclusively in same-sex relationships
OR

agree to avoid impregnating his partner from the Screening Visit until 6 months after 
the administration of IMP, AND
use a highly effective contraceptive method as required by local regulation or practice 
if his female partner is of childbearing potential. The contraceptive method must be 
used from the Screening Visit until 6 months after the administration of IMP and the 
contraceptive method to be used as an additional measure by his partner must include 
one of the following: intrauterine device; contraception implant; progesterone-only 
pills; injectable progestogen (Depo-Provera®); combination hormonal contraceptive 
method (tablets, patches, or vaginal ring with both oestrogen and progestogen), OR
have been surgically sterilized prior to the Screening Visit, OR
have a partner who had her last natural menstruation 24 months prior to the 
Screening Visit, OR
have a partner who had a hysterectomy prior to the Screening Visit, OR
have a partner who was surgically sterilized prior to the Screening Visit
AND

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not donate sperm until ≥6 months after the administration of IMP
16. The patient has provided a signed optional subset-specific Informed Consent Form or an
optional biobank Informed Consent Form, if applicable.
Exclusion Criteria
1.
The patient has previously been enrolled in this study.
2.
The patient has participated in a clinical study <30 days prior to the Screening Visit.
3.
The patient has been previously dosed with an anti-PACAP ligand -targeting antibody.
4.
The patient is a member of the study personnel or of their immediate families or is a 
subordinate (or immediate family member of a subordinate) to any of the study 
personnel.
5.
The patient is pregnant, planning to become pregnant, or breastfeeding.
6.
The patient has known hypersensitivity or intolerance to any of the IMPs or their 
excipients.
7.
The patient has a history of severe drug allergy or hypersensitivity.  Hay fever is allowed 
unless it is active.
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, cluster headache, 
headache attributed to trauma or injury to the head and/or neck, paroxysmal hemicrania, 
short-lasting unilateral neuralgiform headache attacks, hemicrania continua, primary 
thunderclap headache, primary stabbing headache, nummular headache, new daily 
persistent headache, hypnic headache, trigeminal neuralgia, or unusual migraine subtypes 
such as hemiplegic migraine (sporadic and familial), recurrent painful ophthalmoplegic 
neuropathy, migraine with brainstem aura, or migraine with neurological 
accompaniments that are not typical of migraine aura (diplopia, altered consciousness, or 
long duration).
11. The patient has a lifetime history of psychosis, bipolar mania, or dementia.  Patients with 
other psychiatric conditions whose symptoms are not controlled or who have not been 
adequately treated for a minimum of 6 months prior to screening are also excluded.
12. The patient has a current diagnosis or history of substance or alcohol use disorder
(DSM-5® criteria) <24 months prior to the Screening Visit or substance use deemed 
significant by the investigator (excluding nicotine or caffeine).
13. The patient has reported current use of, or has tested positive for, drugs of abuse (cocaine,
amphetamines, phencyclidine, propoxyphene).
14. 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.
15. 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 
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16. The patient has a history of cancer, other than basal cell or Stage 1 squamous cell 
carcinoma of the skin or adequately treated cervical intraepithelial neoplasia, that has not 
been in remission for >5 years prior to the dose of IMP.
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 (including 
autoimmune), rheumatological, or ocular disorders.
18. The patient has a history of clinically significant cardiovascular disease, including 
uncontrolled hypertension, vascular ischaemia, or thromboembolic events (for example, 
cerebrovascular accident, deep vein thrombosis, or pulmonary embolism).
19. The patient has had surgery or trauma with significant blood loss <3 months prior to the 
dose of IMP.
20. The patient has donated blood <3 months prior to the dose of IMP.
21. The patient takes or has taken recent or concomitant medication that is disallowed or has 
not met the restrictions for a medication that is 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.
22. The patient has one or more clinically significant out-of-range vital signs at the Screening 
Visit.
23. The patient has orthostatic hypotension, defined as a decrease in systolic blood pressure 
≥20 mmHg from supine to standing, at the Screening Visit or at the Baseline Visit.
24. The patient has a body mass index (BMI) >30 kg/m2 at the Screening Visit.
25. The patient has previously tested positive for human immunodeficiency virus (HIV).
26. The patient has tested positive for hepatitis C virus antibody (anti-HCV) or has been 
tested for hepatitis B serology and is confirmed to have acute or chronic infection (refer 
to Appendix III for interpretation).
27. 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 or aspartate aminotransferase value >2 times the 
upper limit of the reference range
28. The patient has, at the Screening Visit, an abnormal electrocardiogram (ECG) that is, in 
the investigator’s opinion, clinically significant.
29. The patient has a heart rate-corrected QT interval (QTc) >450 ms (Fridericia’s correction) 
at the Screening Visit, as calculated by the central reading vendor and evaluated by the 
investigator.  The ECG may be repeated if any of the values are out of range or abnormal.
30. 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 within the past 12 months or answering: "yes" to suicidal behaviour 
within the past 12 months).

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31. The patient has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, tolerability, or efficacy, or interfere with the 
conduct or interpretation of the study.
32. The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
5.4
Withdrawal Criteria
A patient must be withdrawn from the study if:
!
The patient withdraws their 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 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 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.
!
The patient experiences an anaphylactic reaction or another serious and/or severe 
hypersensitivity reaction to the IMP infusion, as assessed by the investigator. If the event 
occurs during the infusion, the infusion must be discontinued immediately.
!
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.
!
Any site personnel break the randomization code for that patient.
!
The patient becomes pregnant.
Patients who withdraw will not be replaced.
6
Investigational Medicinal Products
6.1
Treatment Regimen
Patients will be randomly allocated via a centralized randomization system to one of three 
treatment groups: Lu AG09222 
 Lu AG09222 
or placebo, in a ratio of 2:1:2.
The patient will receive IMP at the Baseline Visit with either Lu AG09222 
 
Lu AG09222 
or placebo by IV infusion.
6.2
IMP, Formulation and Strength
The IMP supplied by Lundbeck in this study is:
!
Lu AG09222 solution for injection/infusion
CCI
CCI
CCI
CCI
CCI

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6.4
Method of Assigning Patients to Treatment
The IRT will be used in this study.  Each patient will be assigned a screening number by the 
IRT, and that number will be used to identify the patient throughout the study.  
Randomization of the patient will be performed in the IRT.  The IRT allocates the patient to a 
treatment group and assigns the patient a randomization number in accordance with the 
specifications from Biostatistics, H. Lundbeck A/S.
Randomization will be stratified by region (North America versus Europe)
 
6.5
IMP Accountability
IMP accountability is documented in the IRT by the unblinded clinical research associate 
(CRA).
The investigator and the pharmacist must agree to only dispense IMP to patients enrolled in 
the study.  The unblinded pharmacist must maintain an adequate record of the receipt and 
distribution of the IMP.  This record must be available for inspection by the unblinded CRA 
at any time.
6.6
Unblinding Procedures
Global Patient Safety, H. Lundbeck A/S, 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 
complete the visit as a Withdrawal Visit; otherwise, the patient will be asked to have a 
Withdrawal Visit.
6.7
Post-study Access to IMP(s)
Patients in the study will have access to appropriate medical care after they complete or 
withdraw from the study.
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7
Concomitant Medication
Concomitant medication is any medication other than the IMP that is taken during the study
up until the Safety Follow-up 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), herbal remedies, 
non-pharmacological interventions, vitamin and mineral supplements for the treatment of 
migraine taken and substance use <3 months prior to the Screening Visit must be recorded in 
the electronic case report form (eCRF) at the first visit.  Any changes (including reason for 
changes) in concomitant medication and non-pharmacological interventions must be recorded 
at each subsequent visit. Any changes in substance use must be collected at selected visits 
until the Safety Follow-up/Withdrawal Visit.
Vaccinations (including COVID-19 vaccines) are allowed provided the vaccinations have 
been completed for at least 14 days prior to the Screening Visit. Vaccinations during the 
study are allowed providing the vaccination is received at least 3 days after the IMP 
administration. The vaccinations, including brand names, if used during the study must be 
reported as concomitant medications.
Details of all migraine preventive treatment failure medications (prescription and 
over-the-counter) taken within 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 was 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.
8
Study Visit Plan
8.1
Overview
An overview of the procedures and assessments to be conducted during the study and their 
timing is presented in Panel 2.  Further details are in chapter 9.
Appropriate risk assessment and mitigations will be done in case of restrictions due to 
COVID-19, which will be described in detail in a separate COVID-19 mitigation plan.
The Screening Visit (Visit 1) is performed 28 to 30 days before the Baseline Visit (Visit 2).
At the Baseline Visit (Visit 2), the IMP is administered.  The Primary Outcome Visit (Visit 4) 

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is performed 4 weeks after the Baseline Visit.  A Safety Follow-up Visit (Visit 6) is 
performed 8 weeks after the Primary Outcome Visit.
At the visits, all assessments may be completed over a maximum of 2 consecutive days (with 
the exception of PROs - see paragraph below); if so, the first day is considered the “visit” day 
according to the schedule.
If the date of a visit does not conform to the schedule, subsequent visits should be planned to 
maintain the visit schedule relative to the Baseline Visit.
Patients will record eDiary headache data on a daily basis from the Screening Visit until the 
Safety Follow-up Visit or Efficacy Follow-up/Withdrawal Visit.  At each visit, a compliance 
check of eDiary (based on eDiary reporting) will be conducted.  Additionally, ongoing 
evaluation of eDiary compliance will be performed by the site and more frequent contact with 
patients may be needed in case of non-compliance.  See section 9.2.1.2 for further details on 
eDiary.
Patients will complete the PROs in alignment with scheduled visit dates. PROs scheduled at 
the Baseline Visit (Visit 2) must be completed in the clinic at the visit date and before the 
infusion. PROs scheduled in alignment with all other visits can be completed on the day or 
within 3 days prior to the scheduled visit date. See section 9.2.1 for further details on PROs.
Patients who withdraw prior to the Primary Outcome Visit (Week 4), except for those who 
withdraw their consent, will have a Withdrawal Visit as soon as possible, an Efficacy Follow-
up (Phone Contact) Visit at Week 4, and a further Safety Follow-up Visit at 12 weeks after 
administration of the IMP (the Baseline Visit). If the Withdrawal Visit takes place at Week 4, 
an Efficacy Follow-up (Phone Contact) Visit at Week 4 is not required (see section 8.10).
Visit 3, Visit 4 (Primary Outcome Visit), Visit 5, and Withdrawal Visit can be conducted as a 
clinic visit to the site by the patient or can be provided as a home visit by a healthcare 
provider/study site staff with or without a televisit through teleconferencing. Before these 
visits are conducted, patients will have the option to choose the types of visits to be conducted 
and these are allowed to be changed during the study.  The type of visits conducted must be 
recorded in the eCRF.  Further information on the type of visits will be provided in the Site 
Guide for Off-Site Nursing Services and TeleVisit Solutions Site Reference Guide.
After completing or withdrawing from the study, the patient must be treated in accordance 
with usual clinical practice.
8.2
Screening Visit (Visit 1)
The Screening Visit must be conducted as a visit to the site. Signed informed consent must be 
in place before any study-related assessments are performed (including collection of relevant 
documentation from the patient’s treating physician) and may be obtained prior to the 
Screening Visit. See section 9.1 for further details on screening assessments and chapter 12
for further details on relevant documentation from the treating physician.

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The withdrawal visit does not apply if a patient withdraws during the safety follow-up period
(for whatever reason). Then 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.
8.10
Efficacy Follow-up Visit (Telephone Contact)
The Efficacy Follow-up Visit is conducted as a telephone contact at Week 4 and applies to 
patients who withdraw from the study during the treatment period and prior to Week 3, except 
for those who withdraw their consent.
If the Withdrawal Visit takes place during the treatment period and prior to Week 3, then the 
eDiary assessments should continue on a daily basis until the Efficacy Follow-up Visit 
(Week 4).
At the Efficacy Follow-up Visit, a compliance check of the eDiary will be conducted. The
eDiary closeout will take place at the Efficacy Follow-up Visit. Patients will not be required 
to complete the PRO assessments. Details will be provided in a separate eDiary and PRO 
training material. Adverse events, concomitant medication (prescription and
non-prescription), and non-pharmacological interventions will be collected.
If the Withdrawal Visit takes place at Week 4, an Efficacy Follow-up (telephone contact) 
Visit at Week 4 is not required and the eDiary closeout must take place at the Withdrawal 
Visit (see section 8.9).
8.11
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
9.1
Screening and Baseline Procedures and Assessments
9.1.1
Demographics and Baseline Characteristics
Prior to enrolling a patient in the study, the investigator must ascertain that the patient meets 
the selection criteria.
The following assessments will be performed after the Informed Consent Form has been 
signed:

Demographics (age, sex, race)

Migraine history (including diagnosis of migraine and MOH) *

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Panel 4
ICHD-3 Guidelines for Migraine1
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 (e.g.,
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.
ICHD-3 = International Classification of Headache Disorders Third Edition.
9.1.3
Classifications for Eligibility 
Fulfilment of criteria for migraine, according to the eligibility criteria in this protocol, will be 
confirmed via prospectively collected information in the eDiary during the screening period, 
i.e., migraine occurring on 
and headache occurring on ≤26 days. Prior to 
randomisation, the investigator will review the data in the eDiary Eligibility Report to 
determine if eligibility criteria are fulfilled.
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9.5
Safety Assessments
9.5.1
Adverse Events
The patients will be asked a non-leading question (for example, “how do you feel?”, “how 
have you felt since your last visit?”) at each visit, starting at the Screening Visit.  Adverse 
events (including worsening of concurrent disorders, new disorders, and pregnancies) either 
observed by the investigator or reported spontaneously by the patient will be recorded, and the 
investigator will assess the seriousness and the intensity of each adverse event and its 
relationship to the IMP.  Results from relevant tests and examinations, such as 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.
9.5.2
Clinical Safety Laboratory Tests
The clinical safety laboratory tests are listed in Panel 5.
Panel 5
Clinical Safety Laboratory Tests
Haematology
Liverb
Serologyc,i
B-haemoglobin
B-erythrocyte count
B-total leucocyte count
B-neutrophilsa
B-eosinophilsa
B-basophilsa
B-lymphocytesa
B-monocytesa
B-thrombocyte count
S-total bilirubin
S-alkaline phosphatase
S-alanine aminotransferase
S-aspartate aminotransferase
S-gamma-glutamyl transferase
S-HBsAg
S-anti-HCV
S-anti-HBs
S-anti-HBc
Infection
S-C-reactive protein
Other
S-creatine phosphokinase
S-cardiac troponins (TnT, TnI)
Electrolytesb
Kidneyb
Urineg
S-sodium
S-potassium
S-creatinine
B/S-urea nitrogen
U-protein (dipstick)
U-glucose (dipstick)
U-blood (dipstick)
Endocrine and Metabolicb
Lipidsb,d
Pregnancye and Menopausef
S-albumin
S-glucosed
B-HbA1c
S-TSHc,h
S-low-density lipoprotein
S-high-density lipoprotein
S-triglycerides
S-cholesterol (total)
S--hCGe
U-pregnancy dipsticke
S-FSHc,f
anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B surface antibody; anti-HCV = hepatitis C virus 
antibody; B = blood; -hCG = beta-human chorionic gonadotropin; FSH = follicle-stimulating hormone; 
HBsAg = hepatitis B surface antigen; S = serum; TSH = thyroid-stimulating hormone; U = urine
a
Count and % of total leucocytes.
b
Clinical chemistry.

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c
Performed at the Screening Visit only.
d
Fasting (i.e., 6 hours prior to sample collection), when possible.
e
Only for women of childbearing potential.  Pregnancy test at the Screening Visit and the Safety Follow-up 
Visit is to be conducted using serum β-hCG. At Visit 2, Visit 4 and Withdrawal Visit, urine pregnancy 
testing will be performed, and, in case of a positive finding, further confirmatory testing will be performed 
via serum β-hCG.
f
Only for women of non-childbearing potential who have had her last natural menstruation ≥12 months prior 
to the Screening Visit.
g
If urine dipstick is positive, a urine microscopic panel will be conducted.
h
In case of abnormal TSH, reflex testing of triiodothyronine (T3) and thyroxine (T4) will be conducted.
i
In case of positive or indeterminate results, confirmatory testing will be performed including viral load.
Blood samples for the clinical safety laboratory tests will be collected as outlined in Panel 2.
The blood samples will be analysed at the central laboratory.
Urine samples will be collected and analysed at the central laboratory.
The investigator must review (initial and date) the results of the clinical safety laboratory tests 
as soon as possible after receipt of those results.  Out-of-range values must be interpreted by 
the investigator as “not clinically significant” or “clinically significant” with a comment 
concerning the planned follow-up.  Tests for clinically significant out-of-range values must be 
repeated, or an appropriate clinical follow-up must be arranged by the investigator and 
documented on the laboratory report, until the value has stabilized or until the value has 
returned to a clinically acceptable value (regardless of relationship to the IMP).  A patient 
with a value that is out of range at the Primary Outcome or Withdrawal Visit and considered 
clinically significant must be followed for up to 12 weeks after the out-of-range value 
occurred or 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.
9.5.3
Vital Signs
The investigator may appoint a designee (for example, nurse or paramedic) to measure vital 
signs, provided this is permitted according to local regulations and provided the investigator 
has trained the designee how to measure vital signs.  The investigator must take responsibility 
for reviewing the findings.
Vital signs, including blood pressure, pulse, respiratory rate, and body temperature, must be 
assessed prior to blood sampling.
Pulse and blood pressure will be measured using a standard digital meter. Pulse rate and blood 
pressure will be measured in the following order: supine and standing after the patient has 
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Respiratory rate will be measured by counting the number of breaths over a full minute.
Body temperature will be measured by an ear thermometer.
Any out-of-range vital sign considered clinically significant by the investigator must be 
recorded as an adverse event on an Adverse Event Form.
9.5.4
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.
9.5.5
Electrocardiograms
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.  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.
If the ECG is out of the reference range, it is the investigator’s responsibility to assess the 
value as “Normal,” “Abnormal Not Clinically Significant,” or “Abnormal Clinical 
Significant” and handle it in the appropriate manner.  The investigator has the final decision 
on the interpretation of the ECG results.
All Abnormal (both “Abnormal Not Clinically Significant ECGs” and “Abnormal Clinically 
Significant ECGs”) must be described in words with a diagnosis or value (e.g., Second-degree 
AV-Block type Wenckebach) in the eCRF.
Any abnormal ECG result or out-of-range ECG parameter value and judged “Abnormal 
Clinically Significant ECGs” by the investigator must also be recorded as an adverse event on 
an Adverse Event Form.
9.5.6
Physical and Neurological Examinations
For the Baseline Visit, the examinations are to be conducted prior to the infusion.
The investigator may appoint a designee to be primarily responsible for performing the 
physical and neurological examinations, such as a physician assistant or nurse practitioner (as 
applicable), provided this is permitted according to local regulations and documented on the 

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site delegation log. The investigator must take responsibility for reviewing the findings.
Whenever possible, the same individual should perform all the examinations.
The physical examination (including height at the Screening Visit only) must, at a minimum, 
include an examination of appearance, extremities, skin (including signs of purpura and 
neurological assessments for any new onset of paraesthesia or dysaesthesia), head, neck, eyes, 
ears, nose, throat, lungs, chest, heart, abdomen, genito-urinary system, and musculoskeletal 
system. Note for signs of purpura, or examination of paraesthesia, dysaesthesia, or genito-
urinary system:

Self-reported symptoms are sufficient for signs of purpura in the intimate areas (i.e., 
genito-urinary or breast area). If the patient reports any symptoms, he/she must have an 
objective examination by a physician.

Self-reported symptoms are sufficient for the examination of paraesthesia and 
dysaesthesia (no need for objective examination).

For the genito-urinary system, a full gynaecological examination should only be 
performed if warranted by symptoms or medical history.
The neurological examination must cover the following areas: mental status, examination of 
all cranial nerves, the motor system, reflexes, the sensory system, and the cerebellar functions.  
Any abnormal finding or out-of-range value considered clinically significant by the 
investigator must be recorded as an adverse event on an Adverse Event Form.
9.5.7
Columbia-Suicide Severity Rating Scale
The C-SSRS is a ClinRO.  The C-SSRS is a semi-structured interview developed to 
systematically assess suicidal ideation and behaviour of patients participating in a clinical 
study.58  The C-SSRS has 5 questions addressing suicidal ideation, five sub-questions 
assessing the intensity of ideation, and four questions addressing suicidal behaviour. For this 
study, the following versions of the scale are used: the “Baseline/Screening” version will be 
used at the Screening Visit and the “Since last visit” version will be used 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.
For a rater to be allowed to administer the C-SSRS, the rater must complete the training by 
Dr. Kelly Posner’s group (at Columbia University) and the training assigned by the CRO 
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10 Adverse Events
10.1
Definitions
10.1.1
Adverse Event Definitions60
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, safety COAs), 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 – is any adverse event that:

results in death

is life-threatening (this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death had it been more severe)

requires inpatient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is medically important (this refers to an event that may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent any of the SAEs defined above)
Examples of medically important events are intensive treatment for allergic bronchospasm; 
blood dyscrasia or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
Planned hospitalizations or surgical interventions for a condition that existed before the 
patient signed the Informed Consent Form and that did not change in intensity are not adverse 
events.  Emergency room visits that do not result in admission to the hospital are not 
necessarily SAEs; however, they must be evaluated to determine whether they meet any of the 
SAE definitions (for example, life-threatening or other serious [medically important] event).
Non-serious adverse event – is any adverse event that does not meet the definition of an SAE.
If there is any doubt as to whether an adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an SAE.

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Suspected unexpected serious adverse reaction – is any adverse event that is assessed as 
serious, unexpected (its nature or intensity is not consistent with the current version of the 
Investigator’s Brochure42) and related to a medicinal product by either the investigator or 
Lundbeck.
Overdose – is a dose taken by a patient that exceeds the dose prescribed to that patient.  Any 
overdose (and associated symptoms) must, at a minimum, be recorded as a non-serious 
adverse event.
10.1.2
Adverse Event Assessment Definitions
Assessment of Intensity
The investigator must assess the intensity of the adverse event using the following definitions, 
and record it on the Adverse Event Form:

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.
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.
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.

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10.2
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.
If the partner of a man participating in the study becomes pregnant, the outcome of the 
pregnancy should be followed if the partner agrees.  The partner must sign a pregnant partner 
informed consent form to allow the investigator to collect information to report to Lundbeck.
The investigator must follow up on the outcome of the pregnancy and report it on a 
Pregnancy Form (paper).  The follow-up must include information on the neonate at least up 
until the age of 1 month.
10.3
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.
10.4
Reporting Serious Adverse Events
The investigator must report SAEs to Lundbeck immediately (within 24 hours) after 
becoming aware of them by completing a Serious Adverse Event Form.

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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 sudden unexpected adverse reactions 
(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 Directive61
and in Norway, Liechtenstein, 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.
10.5
Treatment and Follow-up of Adverse Events
Patients with adverse events must be treated in accordance with usual clinical practice at the 
discretion of the investigator.
The investigator must follow up on non-serious adverse events until resolution or the Safety 
Follow-up Visit/Contact, whichever comes first.  At the Safety Follow-up Visit/Contact, 
information on new SAEs, if any, and stop dates for previously reported adverse events must 
be recorded.
The investigator must follow up on all SAEs until the patient has recovered, stabilized, or 
recovered with sequelae, and report to Lundbeck all relevant new information using the same 
procedures and timelines as those for the initial Serious Adverse Event Form.
SAEs that are spontaneously reported by a patient to the investigator after the Safety Follow-
up Visit/Contact must be handled in the same manner as SAEs that occur during the study.  
These SAEs will be recorded in the Lundbeck safety database.
The investigator must follow up on patients with a clinically significant out-of-range clinical 
safety laboratory test value at the Primary Outcome or Withdrawal Visit for up to 12 weeks.  
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 

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by the Safety Follow-up 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.
10.6
Data Monitoring Committee
The DMC will consist of medical doctors with speciality relevant to the fields of neurology,
immunology and rheumatology.  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 DMC
Charter.
11 Data Handling and Record Keeping
11.1
Data Collection
11.1.1
Electronic Case Report Forms
eCRFs will be used to collect all the data related to the study, except the external data 
described in section 11.1.3.
The eCRFs use third party software (Rave®) to capture data via an online system on a 
computer.  When the investigator enters data in the eCRF (ideally during the visit or as soon 
as possible [<3 days] thereafter), the data will be recorded electronically in a central database 
over encrypted lines, and all entries and modifications to the data will be logged in an audit 
trail.  Access to the system will only be granted after appropriate and documented training.  
Written instructions for using the system will be provided along with the training.
Electronic signatures will be used where signatures are required on pages and/or visits.  
Automated data entry checks will be implemented where appropriate; other data will be 
reviewed and evaluated for accuracy by the sponsor and/or representatives from PPD.  All 
entries, corrections, and changes must be made by the investigator or a delegate.
11.1.2
Patient Binders
11.1.2.1
Use of Patient Binders
A Patient Binder will be provided for each patient.  The Patient Binder contains different 
types of source documents, organized by visit and type.  A ballpoint pen with waterproof ink 
must be used to enter information in the Patient Binder.

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11.1.2.2
Serious Adverse Event Fallback Forms
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed.
11.1.3
External Data
All electronic data will be transferred using a secure method accepted by Lundbeck.
The following electronic data will be transferred by the vendor and kept in a secure 
designated storage area outside the eCRF:
!
eDiary data
!
COA data
!
ECG data
!
Clinical safety laboratory data (including blood sampling for serology [HBsAg, anti-HBc, 
anti-HBs, anti-HCV]) and blood sampling for other screening [e.g., β-hCG, FSH])
!
IMP quantification data
!
quantification data
!
analysis data 
!
data
!
ADA and NAb data
!
11.2
Database Release
The database will be declared to be complete and accurate by mutual agreement between the 
CRO and Lundbeck.  Once the database release has been approved by both parties, the 
database will be released and unblinded in accordance with CRO procedures, as agreed by 
Lundbeck.
11.3
Retention of Study Documents at the Site
11.3.1
eCRF Data
If a site closes before the study has been completed, the investigator will continue to have 
read-only access to the eCRF until the study has been completed.  After the study has been 
completed, all user access to the eCRF will be revoked.  Renewed access to the eCRF will be 
given if corrections or updates to the database are required.
At the end of the study, the site will be provided with all data related to the site (including 
eCRF data, queries, and the audit trail) using a secure electronic medium; the secure storage 
of these data at the site is the responsibility of the investigator. When confirmation of receipt 
of the data has been received from all sites, all user access to the eCRF will be revoked. If, 
for some reason, the data are not readable for the full retention period (25 years or in 
accordance with national requirements, whichever is longer), the investigator may request that 
the data be re-sent.
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11.3.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator TMF for at 
least 25 years after the Clinical Study Report has been approved or in accordance with 
national requirements, whichever is longer.  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.
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 migraine history, general 
medical history, recent medication taken, and previous migraine preventive medication 
treatment failures (see section 9.1.1 for definition) within the 10 years prior to the Screening 
Visit. The signed Informed Consent Form must be obtained prior to the Screening Visit if the 
investigator/designee needs to obtain relevant documentation from the patient’s treating 
physician.  The investigator can delegate the task of collecting this information to appropriate 
site staff, but it is still the investigator’s responsibility to ensure that the patient fulfils the 
eligibility criteria (this includes checking that adequate documentation has been obtained) 
prior to screening the patient.
Acceptable documented evidence of previous migraine preventive medication failures is as 
follows:

Medical record with medication’s name, treatment stop and start dates, 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 and medical records are not 
available/sufficient, the investigator/designee can either:

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Interview the treating physician to confirm the above information and document the 
interview with date and name of treating physician in the medical records, OR
Interview the patient to obtain the above information, then contact the treating physician 
to confirm the information and document the contact in the medical records with date 
and name of treating physician.
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.
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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Safety will be reported based on the APTS. Efficacy in the treatment period will be reported 
for the FAS.  Maintenance of effect covering efficacy in the treatment period as well as the 
safety follow-up period will be reported for the FAS-LT.
16.3
Descriptive Statistics
In general, summary statistics (n, arithmetic mean, standard deviation, median, lower and 
upper quartiles, minimum and maximum values) will be presented for continuous variables 
and counts and, if relevant, percentages will be presented for categorical variables.
16.4
Patient Disposition
Patient disposition will be summarized by treatment group and include the number of patients 
in the APTS who completed or withdrew prior to Week 4, as well as the number of patients in 
each analysis set described in section 16.2.
The number of patients who completed or withdrew from the study will also be summarized.
The number of patients who withdrew prior to Week 4 will be summarized by treatment 
group and primary reason for withdrawal as well as by treatment group and all reasons for 
withdrawal.
The number of patients who did not complete the study will be summarized by treatment 
group and the reason for withdrawal from the study.
16.5
Demographics and Baseline Characteristics
Demographics (sex, age, and race), baseline characteristics (height, weight, and BMI), 
baseline efficacy variables, and other disease characteristics (including, but not limited to,
headache location, 
score, CM or EM, number of failed preventive migraine 
medications) will be summarized by treatment group.
16.6
Recent and Concomitant Medication
Recent and concomitant medication will be summarized by anatomical therapeutic chemical 
code and generic drug name by treatment group.
16.7
Exposure
All patients in the APTS are expected to receive only one single infusion of the IMP. The 
number of patients who received the treatment, number of patients with infusion interruption, 
number of days in the study, and duration of infusion will be summarized by treatment group.
Randomized patients whose infusion took more than 45 minutes and patients who had their 
infusion interrupted will be listed with treatment group, infusion start date/time and end 
date/time, IRRs, total volume infused, and reasons, if any.
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16.8
Efficacy Analyses
16.8.1
General Efficacy Analysis Methodology
All the statistical tests of the efficacy endpoints will be one-sided tests performed at the 5% 
significance level and all confidence intervals (CIs) will be 90% CIs, unless otherwise 
specified.
16.8.2
Primary Analysis of the Primary Endpoint
The clinical question to be answered with the primary analysis is: does Lu AG09222 prevent 
migraine in the target patient population?
The estimand that will be used to answer the clinical question is: the effect of Lu AG09222 
that would be seen regardless of whether treatment was administered per protocol and if no 
preventive migraine therapy was used and all patients were able to continue in the study.
The treatments that will be compared are the treatment of interest, Lu AG09222, and the 
reference treatment placebo.
The population that will be evaluated is the FAS including the target population as described 
in this document.
The variable on which the primary analysis is based is the primary variable, change from 
baseline in the number of MMDs over Weeks 1 to 4, which summarizes eDiary data across 
Weeks 1 to 4. If acute rescue medication is successfully used during a day, this day counts as 
a migraine day (see section 9.1.2). See section 9.1.3 for definition of a Migraine Day, 
Headache Day and Compliant Day during the Screening Period. The same definitions will be 
used for the treatment period.
The following intercurrent events (IEs) have been identified:
!
Use of acute rescue medication
!
Use of preventive migraine therapy
!
Treatment not administered per protocol
These IEs will be taken into account as follows: use of acute rescue medication or preventive 
migraine therapy (different from investigational medication) is taken into account using a 
composite strategy. Incorrect administration of treatment is handled using a treatment policy 
strategy. 
The population level summary for the primary analysis is: the least-squares mean difference 
in change from baseline in the number of MMDs (Weeks 1 to 4) between the high dose of 
 and placebo, based on an analysis of covariance (ANCOVA) with baseline MMDs as 
covariate and treatment (placebo, low dose, high dose), population (EM or CM), and an 
interaction between the stratification factors (region and 
 
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Adverse events, sorted by system organ class and preferred term, will be summarized by 
treatment group.
Allocation of TEAEs to Study Periods
TEAEs may be allocated to study periods (these will be defined in the SAP).
16.9.2
Analysis of Other Safety Endpoints
The clinical safety laboratory test values, vital signs, ECG parameter values, weight and 
development of ADA (including NAb) will be summarized by treatment group.  Potentially 
clinically significant values will be flagged and summarized.
The C-SSRS scores will be presented using the C-SSRS categorization. The numbers and 
percentages of patients with lifetime, baseline, or post-baseline suicide-related events based 
on the C-SSRS scores will be summarized by treatment group.
The individual C-SSRS scores will be listed, and patients with at least one suicide-related 
event based on the C-SSRS scores will be flagged.
Missing C-SSRS scores will not be imputed.
16.10 Sample Size and Power
Simulations were used to determine a sample size that ensured at least 80% power at a 
one-sided 5% significance level for detecting an effect of 2.1 on the 
 dose when using 
an ANCOVA with baseline MMD as a covariate and treatment and population (EM or CM) 
as fixed factors. A population with 30% EM and 70% CM patients was assumed with 
standard deviations of 3.8 and 6.1, respectively, which resulted in a standard deviation of 5.6
for the full population. The resulting required sample size is 86 patients per arm for the 
dose and placebo. No formal power calculation was performed for the 
 dose. 
A sample size of 43 per arm was considered sufficient to evaluate the relevant endpoints for 
this dose, which results in a randomization ratio of 2:1:2.  Adjusting for an expected 5% 
dropout rate, a total sample size of 230 will be required.
The cap of 30% for the EM population results in a similar precision (standard error) for the 
treatment estimates for the EM and CM populations.
Simulations are based on 10000 runs.
16.11 Statistical Analysis Plan
An SAP 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.
CCI
CCI
CCI

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17 Clinical Study Report and Publications
17.1
Data Ownership
The data collected in this study are the property of Lundbeck.
17.2
Clinical Study Report
Upon completion of the study, a Clinical Study Report will be prepared by Regulatory 
Medical Writing, H. Lundbeck A/S.
17.3
Summary of Clinical Study Results
Upon completion of the study and when the study results are available, the patient has the 
right to be informed by the investigator about the overall study results.
17.4
Publications
The results of this study will be submitted for publication.
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 
ICMJE.62
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
19.1
Site Agreements
The financial agreements with each site are addressed in one or more documents.  Both 
parties must sign the agreements before each site is initiated.

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19.2
Financial Disclosure
All the investigators, including sub-investigators, and raters participating in the study must 
complete a Financial Disclosure Form.
19.3
Equipment
Equipment owned or rented by 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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like attacks in patients with migraine without aura. Brain. 2009 Jan;132(Pt 1):16-25.
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of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-
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38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. 
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migraine. Ann Clin Transl Neurol. 2014 Dec;1(12):1036-1040.
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Pain. 2018 Mar;19(1):21
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cerebral arteries and cranial ganglia. Neuroreport. 2002 Mar 25;13(4):507-509.
47. Vaudry D, Gonzalez BJ, Basille M, Yon L, Fournier A, Vaudry H. Pituitary adenylate cyclase-
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polypeptide: IUPHAR review 1. Br J Pharmacol. 2012 May;166(1):4-17

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Appendix I
Clinical Study Protocol
Authentication and Authorization

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Clinical Study Protocol
Authentication and Authorization
Study title:
Interventional, randomized, double-blind, parallel-group, placebo-controlled study 
of Lu AG09222 for the prevention of migraine in patients with unsuccessful prior 
preventive treatments
Study No.:
19678A
Edition No.:
3.0 (includes all Clinical Study Protocol changes since previous Edition 2.0)
(the version No. in the footer is the system version No.)
Date of edition:
11 July 2022
This document has been signed electronically.  The signatories are listed below.
Authentication
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
International study manager:
Clinical research scientist:
Head of Biostatistics:
Head of Medical Safety:
Authorization
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
Therapeutic Area Lead:
PPD
PPD
PPD
PPD
PPD

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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
Allowed if prescribed for non-migraine indications, if dose and 
regimen have been stable for at least 12 weeks prior to Screening Visit 
and until the Safety Follow-up Visit.
Antidepressants
Allowed if prescribed for non-migraine indications, if dose and 
regimen have been stable for at least 12 weeks prior to Screening Visit 
and until the Safety Follow-up Visit
Antihypertensives
Allowed if prescribed for non-migraine indications, if dose and 
regimen have been stable for at least 12 weeks prior to Screening Visit 
and until the Safety Follow-up Visit
Anti-impotence agents
Allowed if the dose has been stable for at least 12 weeks prior to the 
Screening Visit and is expected to be maintained until the Safety
Follow-up Visit (Week 12).
Anti-inflammatory agents
Allowed:
NSAID: Allowed as acute treatment for migraine (see restrictions 
under anti-migraine agents). Allowed if prescribed for non-migraine 
indications (e.g., acetylsalicylic acid for cardiovascular disease 
prevention or for treatment of infections).
Steroids: Inhalation steroids are allowed if prescribed, e.g., for asthma, 
provided the dose and regimen have been stable for at least 12 weeks 
prior to the Screening Visit and expected to be maintained until the 
Safety Follow-up Visit (Week 12).
Disallowed:
Steroids: Do not use topical steroids <1 week prior to the Screening 
Visit until the Safety Follow-up Visit (Week 12). For systemic steroids 
See restrictions under immunosuppressants.
Anti-migraine agents
Allowed with restrictions:
Acute treatment of migraine (prescription or over-the-counter 
medication recommended by a healthcare professional) is allowed 
provided the treatments used have been stable for at least 14 days prior 
to the Screening Visit and expected to be maintained until the Safety 
Follow-up Visit (Week 12). At the discretion of the Investigator, on a 
case-by-case basis, changes that might be clinically warranted may be 
made after the Baseline Visit.
Any medications in preventive migraine treatment classes that are 
prescribed for medical conditions other than migraine prevention are 
allowed if they have been stable in terms of dose and regimen for at 

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Drug Class
Details
least 12 weeks prior to the Screening Visit and until the Safety Follow-
up Visit.
Disallowed:
Do not use preventive migraine treatments <1 week prior to the 
Screening Visit until the Safety Follow-up Visit (Week 12).
Do not use oral anti-CGRP treatment <4 weeks prior to the Screening 
Visit and until the Safety Follow-up Visit (Week 12).
Do not use CGRP-directed monoclonal antibodies <24 weeks prior to 
the Screening Visit until the Safety Follow-up Visit (Week 12).
Do not use botulinum toxin for migraine or any other 
medical/cosmetic reason in the head and/or neck region <16 weeks 
prior to the Screening Visit and until the Safety Follow-up Visit 
(Week 12).
Do not use monoamine oxidase inhibitors, ketamine, methysergide, 
methylergonovine, or nimesulide <12 weeks prior to the Screening 
Visit and until the Safety Follow-up Visit (Week 12).
Do not use preventive injectable therapy (e.g., trigger point injections, 
extracranial nerve blocks, or facet joint injections) <8 weeks prior to 
the Screening Visit and until the Safety Follow-up Visit (Week 12).
Hormones
Hormonal therapy (e.g., contraceptives, hormone replacement therapy) 
is allowed provided the dose and regimen have been stable for at least 
12 weeks prior to the Screening Visit and expected to be maintained 
until the Safety Follow-up Visit (Week 12).
Immunosuppressants
Do not use immunosuppressants (e.g., systemic steroids, TNF alpha 
inhibitors, methotrexate) <12 weeks (or at least 5 times the half-life of 
the medication) prior to the Screening Visit and until the Safety 
Follow-up Visit (Week 12).
Nicotine/Tobacco
Allowed provided stable use for at least 14 days prior to the Screening 
Visit and until the Safety Follow-up Visit (Week 12).
Cannabinoids
Are allowed provided a stable dose and regimen have been maintained 
for at least 12 weeks prior to the Screening Visit and are expected to 
be maintained until the Safety Follow-up Visit.
Opioid analgesics
Prescription opiates (including single-ingredient or combination 
medications containing opiates, opioids, tramadol, or tapentadol) are 
allowed provided a stable dose and regimen have been maintained for 
at least 12 weeks prior to the Screening Visit and are expected to be 
maintained until the Safety Follow-up Visit (Week 12). These agents 
are allowed provided use has not exceeded 4 days per month 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 their use 
does not exceed 4 days per month.

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Drug Class
Details
Other interventions and devices for 
the treatment of migraine
Allowed with restrictions:
Non-pharmacological interventions and therapies for the treatment of 
migraine (e.g., behavioural therapy, physical therapy and acupuncture) 
are allowed provided their use has been stable for at least 12 weeks 
prior to the Screening Visit and is expected to be maintained until the 
Safety Follow-up Visit (Week 12).
Disallowed:
Do not use CNS- and migraine-related devices (neuromodulation, 
neurostimulation) <8 weeks prior to the Screening Visit and until the 
Safety Follow-up Visit (Week 12).
Sedatives/hypnotics
Barbiturates (including Fiorinal®, Fioricet®, or any other combination 
containing butalbital) are allowed provided a stable dose and regimen 
have been maintained for at least 12 weeks prior to the Screening Visit  
and are expected to be maintained until the Safety Follow-up Visit 
(Week 12). These agents are allowed provided use has not exceeded 4 
days per month 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.
Benzodiazepines are allowed provided a stable dose and regimen have 
been maintained for at least 12 weeks prior to the Screening Visit and
are expected to be maintained until the Safety Follow-up Visit 
(Week 12).  These agents may be prescribed when considered 
medically indicated during the study (including the screening period) 
and a stable dose and regimen are expected to be maintained.
Vaccinations
Vaccinations (including COVID-19 vaccines) are allowed provided 
the vaccinations have been completed for at least 14 days prior to the 
Screening Visit. Vaccinations during the study are allowed providing 
the vaccination is received at least 3 days after the IMP administration.  
The vaccinations, including brand names, if used during the study 
must be reported as concomitant medications.

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Appendix III
Interpretation of Hepatitis B Serologic Test Results

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Interpretation of Hepatitis B Serologic Test Results
HBsAg
negative
Susceptible
anti-HBc
negative
anti-HBs
negative
HBsAg
negative
Immune due to natural infection
anti-HBc
positive
anti-HBs
positive
HBsAg
negative
Immune due to hepatitis B vaccination
anti-HBc
negative
anti-HBs
positive
HBsAg
positive
Acutely/Chronically infected
anti-HBc
positive
anti-HBs
negative
HBsAg
negative
Interpretation unclear; four possibilities:
1. Resolved infection (most common)
2. False-positive anti-HBc, thus susceptible
3. “Low level” chronic infection
4. Resolving acute infection
anti-HBc
positive
anti-HBs
negative