Clinical trial NCT05133323
Conditions: Migraine
Sponsor: H. Lundbeck A/S
Start date: 2021-11-11; Completion date: 2023-03-16
Enrollment: 237 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Researchers are trying to learn whether a drug called Lu AG09222 can help prevent migraine headaches for people who have not been helped by other treatments that are used to prevent migraines.

People who join this trial have tried 2 to 4 other medications to prevent their migraines, but these medications have not helped them.

When the trial is over, researchers will use this information to find out if the number of migraine days decreased more for the participants who got either dose of Lu AG09222 than for the participants who got the placebo.

Detailed description:
Participants will be randomly allocated to one of 3 treatment groups: Lu AG09222 high dose, Lu AG09222 low dose, or placebo, in a ratio of 2:1:2.

Arms: arm 1: Participants will receive a single high dose of Lu AG09222 by intravenous (IV) infusion. arm 2: Participants will receive a single low dose of Lu AG09222 by IV infusion. arm 3: Participants will receive a single dose of placebo matching to Lu AG09222 by IV infusion.
Interventions: intervention 1: Lu AG09222 intervention 2: Placebo
Intervention descriptions: intervention 1: Lu AG09222 will be administered per schedule specified in the arm. intervention 2: Placebo matching to Lu AG09222 will be administered per schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
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 
Concomitant Medication, Disallowed or Allowed with Restrictions.


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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
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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 
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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
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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
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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 
before the start of study. Raters will complete their designated training curriculum based on 














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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 
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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 
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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.
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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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the International Headache Society for controlled trials of preventive treatment of migraine 
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19. Schytz HW, Olesen J, Ashina M. The PACAP receptor: a novel target for migraine treatment. 
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Headache. 2017 May;57 Suppl 2:56-63.
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drug development – pharmacochemical aspects. Curr Med Chem. 2017;24(33):3649-3665.
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in the human sphenopalatine and otic ganglia. Brain Res. 1999 May 1;826(2):193-199.
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in the human trigeminal ganglion. J Auton Nerv Syst 1999 May 28;76(2-3):176–183.
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the human brainstem. Cephalalgia. 2001 Mar;21(2):96-101.
27. Uddman R, Tajti J, Hou M, Sundler F, Edvinsson L. Neuropeptide expression in the human 
trigeminal nucleus caudalis and in the cervical spinal cord C1 and C2. Cephalalgia 2002
Mar;22(2):112-116.
28. Csati A, Tajti J, Kuris A, Tuka B, Edvinsson L, Warfvinge. Distribution of vasoactive intestinal 
peptide, pituitary adenylate cyclase-activating peptide, nitric oxide synthase, and their receptors 
in human and rat sphenopalatine ganglion. Neuroscience. 2012 Jan 27;202: 158-168.
29. Goadsby PJ, Holland PR, Martins-Oliveira M, Hoffmann J, Schankin C, Akerman S. 
Pathophysiology of migraine: a disorder of sensory processing. Physiol Rev. 2017 Apr;97(2):553-
622.
30. Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina  M. PACAP38 induces migraine-
like attacks in patients with migraine without aura. Brain. 2009 Jan;132(Pt 1):16-25.
31. Amin FMA, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, et al. Investigation 
of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-
activating polypeptide-38. Brain. 2014 Mar;137(Pt 3):779-794.
32. Amin FM, Asghar MS, Guo S, Hougaard A, Hansen AE, Schytz HW, et al. Headache and 
prolonged dilatation of the middle meningeal artery by PACAP38 in healthy volunteers. 
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33. Tuka B, Helyes Z, Markovics A, Bagoly T, Szolcsanyi J, Szabo N, et al. Alterations in PACAP-
38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. 
Cephalalgia. 2013 Oct;33(13):1085-1095.
34. Zagami AS, Edvinsson L, Goadsby PJ. Pituitary adenylate cyclase activating polypeptide and 
migraine. Ann Clin Transl Neurol. 2014 Dec;1(12):1036-1040.
35. Edvinsson L, Tajti J, Szalárdy L, Vecsei L. PACAP and its role in primary headaches. J Headache 
Pain. 2018 Mar;19(1):21
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(PBn) pituitary adenylate cyclase activating polypeptide (PACAP) signaling in the amygdala: 
implication for the sensory and behavioral effects of pain. Neuropharmacology. 2014 Nov;86:38–
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37. Hammack SE, May V. Pituitary adenylate cyclase activating polypeptide in stress-related 
disorders: data convergence from animal and human studies. Biol Psychiatry. 2015 Aug 
1;78(3):167-177.
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reinstatement of cocaine seeking in rats. Neuropsychopharmacology. 2018 Apr;43(5):978-986.
39. Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, et al. Post-traumatic stress 
disorder is associated with PACAP and the PAC1 receptor. Nature. 2011 Feb 24;470(7335):492-
497. 
40. Baun M, Pedersen MHF, Olesen J, Jansen-Olesen I. Dural mast cell degranulation is a putative 
mechanism for headache induced by PACAP-38. Cephalalgia. 2012 Mar;32(4):337-345.
41. Pedersen SH, la Cour SH, Calloe K, Hauser F, Olesen J, Klaerke DA, et al. PACAP-38 and 
PACAP (6–38) degranulate rat meningeal mast cells via the orphan MrgB3-receptor. Front Cell 
Neurosci. 2019 Mar 28;13:114.
42. H. Lundbeck A/S. Investigator’s Brochure: Lu AG09222. current edition.
43. Strother LC, Srikiatkhachorn A, Supronsinchai W. Targeted orexin and hypothalamic 
neuropeptides for migraine. Neurotherapeutics. 2018 Apr;15(2):377-390.
44. Vollesen ALH, Amin FM, Ashina M. Targeted pituitary adenylate cyclase-activating peptide 
therapies for migraine. Neurotherapeutics. 2018 Apr;15(2):371-376.
45. Erdling A, Sheykhzade M, Maddahi A, Bari F, Edvinsson L. VIP/PACAP receptors in cerebral 
arteries of rat: characterization, localization and relation to intracellular calcium. Neuropeptides.
2013 Apr;47(2):85-92.
46. Knutsson M, Edvinsson L. Distribution of mRNA for VIP and PACAP receptors in human 
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-
activating polypeptide and its receptors: from structure to functions. Pharmacol Rev. 2000
Jun;52(2):269-324.
48. Harmar AJ, Fahrenkrug J, Gozes I, Laburthe M, May V, Pisegna JR, et al. Pharmacology and 
functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating 
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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Page 106 of 109
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

SAP_001.pdf: 
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Trial 19678A – Statistical Analysis Plan
Page 1 of 78
Statistical Analysis Plan
Interventional, randomized, double-blind, parallel-group, 
placebo-controlled trial of Lu AG09222 for the prevention of 
migraine in patients with unsuccessful prior preventive 
treatments
Lu AG09222
Trial No.:
19678A
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
SAP date:
29 March 2023
This document is the property of H. Lundbeck A/S and H. Lundbeck A/S is the holder of any and all 
related intellectual property rights, including, but not limited to, copyrights.  This document is 
confidential.  It is not to be copied or distributed to other parties without prior written authorization 
from H. Lundbeck A/S.
PPD
PPD
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Table of Contents
List of Panels and Tables...............................................................................................................6
List of Abbreviations and Definitions of Terms ..........................................................................7
1
Objectives...............................................................................................................................9
2
Trial Design..........................................................................................................................12
3
COVID-19 ............................................................................................................................14
4
Definitions ............................................................................................................................15
4.1
Definition of Baseline................................................................................................15
4.2
Definition of Periods..................................................................................................15
4.3
Definition of Withdrawal...........................................................................................15
4.4
Definition of Planned versus Actual Treatment ........................................................15
4.5
Definition of Region..................................................................................................16
4.6
Definitions for 
, Migraine 
Day, Headache Day, 
.......16
4.6.1
.....................16
4.6.2
Migraine Day..............................................................................................17
4.6.3
Headache Day ............................................................................................18
4.6.4
..........................................................................................18
4.6.5
......................................................................................18
4.6.6
...........................................................................................18
5
Analysis Sets.........................................................................................................................19
6
Descriptive Statistics ...........................................................................................................19
7
Participant Disposition........................................................................................................20
7.1
Summary of Participant Disposition..........................................................................20
7.2
Withdrawals...............................................................................................................20
8
Demographics and Baseline Characteristics.....................................................................20
9
Recent and Concomitant Medication ................................................................................22
10
Exposure...............................................................................................................................23
11
eDiary Compliance ..............................................................................................................23
12
Efficacy.................................................................................................................................23
12.1
General Efficacy Analysis Methodology...................................................................23
12.2
Testing Strategy.........................................................................................................24
12.3
Analysis Methodology for the Primary Endpoint......................................................24
12.3.1
Primary Estimand.......................................................................................24
12.3.2
Strategies for Addressing Intercurrent Events in Primary Estimand..........25
12.3.3
Primary Analysis of the Primary Endpoint ................................................25
12.3.4
Rationale for Selected Analysis Method for the Primary Endpoint...........26
12.3.5
Sensitivity Analyses of the Primary Endpoint ...........................................26
12.3.6
27
12.4
Analysis Methodology for the Secondary Endpoints ................................................27
12.5
...............................................28
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13
Safety ....................................................................................................................................31
13.1
Adverse Events..........................................................................................................31
13.1.1
General Methodology for Adverse Events.................................................31
13.1.2
Coding of Adverse Events..........................................................................31
13.1.3
Classification of Adverse Events ...............................................................32
13.1.4
Presentation of Adverse Events..................................................................32
13.1.5
Presentation of Treatment-emergent Adverse Events ................................32
13.1.6
Presentation of Deaths................................................................................33
13.1.7
Presentation of Serious Adverse Events.....................................................33
13.1.8
Presentation of Adverse Events Leading to Withdrawal............................33
13.1.9
Presentation of Adverse Events Leading to IMP Infusion Interruption .....33
13.1.10
............33
13.2
General Methodology for Other Safety Data.............................................................33
13.3
Clinical Safety Laboratory Test Data ........................................................................34
13.3.1
Data Presentation........................................................................................34
13.3.2
Anti-drug Antibody Including Neutralizing Antibody Assessments .........34
13.3.3
Potential Drug-induced Liver Injury (DILI)...............................................35
13.4
Vital Signs and Weight..............................................................................................36
13.5
ECGs..........................................................................................................................36
13.6
Other Safety Endpoints..............................................................................................36
13.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores.......................36
14
.....................................................................................................................37
15
Pharmacokinetic/Pharmacodynamic Analyses.................................................................38
16
Biomarker analyses .............................................................................................................38
17
Blinded Data Reviews..........................................................................................................38
18
Interim Analyses..................................................................................................................38
19
Sample Size Considerations................................................................................................39
20
Statistical Software..............................................................................................................39
21
Changes to Analyses Specified in the Protocol..................................................................39
21.1
Definition of Periods..................................................................................................39
21.2
Estimand Strategy for the Intercurrent Events...........................................................40
21.3
Analysis Sets..............................................................................................................40
21.4
Primary Analysis of the Primary Endpoint................................................................40
21.5
Sensitivity Analyses of the Primary Endpoint...........................................................40
21.6
.................................41
21.7
...........................................41
21.8
..........................................................42
22
Details on Data Handling....................................................................................................43
22.1
Derived Variables ......................................................................................................43
22.1.1
eDiary.........................................................................................................43
22.1.1.1
Determination of Migraine Days and Headache Days...............43
22.1.1.2
Monthly Migraine Days, 
......................44
22.1.1.3
Migraine/
 Response Variables ...................................46
22.1.1.4
..................46
22.1.1.5
............46
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22.1.1.6
 
.....................................................................................46
22.1.1.7
 
..........................................................47
22.1.1.8
...................................................................47
22.1.2
.....................................................48
22.1.2.1
............................48
22.1.2.2
..........................................48
22.1.2.3
..................................................48
22.1.2.4
.49
22.1.2.5
............................51
22.1.2.6
...............................................................................51
22.1.2.7
.................................51
22.1.2.8
.........................................................................................51
22.1.2.9
.........................................................................................52
22.1.3
Handling of Data After ICE “Use of Preventive Therapy”........................52
22.2
Assigning Data to Visits ............................................................................................52
22.2.1
Safety Variables .........................................................................................52
22.3
Handling Missing or Incomplete Dates/Times ..........................................................53
22.3.1
Missing Headache End Date and Time ......................................................53
22.3.2
Withdrawal Date ........................................................................................53
22.3.3
Medical Disorder Start and Stop Dates ......................................................53
22.3.4
Medication Start and Stop Dates................................................................53
22.3.5
Adverse Event Start and Stop Dates...........................................................54
22.4
Data With Multiple Records......................................................................................55
22.4.1
Dose Changes in Medication......................................................................55
22.4.2
Changes in Intensity or Seriousness of Adverse Events ............................55
References .....................................................................................................................................57
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Appendices
Statistical Analysis Plan Authentication and Authorization ..............................58
Trial Procedures and Assessments.....................................................................60
ICHD-3 Guidelines for Migraine.......................................................................66
.........................................................................................................68
PCS Criteria .......................................................................................................73
............................................77
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List of Panels and Tables
Panel 1 
Objectives and Endpoints ........................................................................................... 9
Panel 2 
Trial Design .............................................................................................................. 14
Panel 3
................................................................................................. 50
Panel 4
............................................................................................ 50
Panel 5
................................................................. 50
Panel 6
Visit Windows - Laboratory Tests, Vital Signs, Body Weight, ECG  and C-SSRS. 52
Table 1
Trial Procedures and Assessments............................................................................ 61
Table 2
PCS Criteria for Clinical Safety Laboratory Tests ................................................... 74
Table 3
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference .................... 75
Table 4
PCS Criteria for ECG Parameters............................................................................. 76
Table 5
................................................... 78
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List of Abbreviations and Definitions of Terms
ADA
anti-drug antibody
ANCOVA
analysis of covariance
APRS
all-patients-randomized set
APTS
all-patients-treated set
BMI
body mass index
CGRP
calcitonin gene-related peptide
CI
confidence interval
CM
chronic migraine
COA
clinical outcome assessment
C-SSRS
columbia suicide severity rating scale
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
eDiary
electronic diary
EM
episodic migraine
FAS
full-analysis set
FAS-LT
full analysis set long term
HD
Headache day(s)
HLGT
high level group term
HLT
high level term
ICE
intercurrent event
IMP
investigational medicinal product
MedDRA
Medical Dictionary for Regulatory Activities 
MD
migraine day(s)
MHDs
monthly headache days
ML
maximum likelihood
MMDs
monthly migraine days
MMRM
mixed model for repeated measurements
MOH
medication overuse headache
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NAb
neutralizing antibody
PACAP
pituitary adenylate cyclase-activating polypeptide
PCS
potentially clinically significant
PD
Pharmacodynamic(s)
PK
pharmacokinetic(s)
QT
specific ECG interval describing ventricular depolarization/repolarization
QTc
heart rate-corrected QT interval
REML
restricted maximum likelihood
SAE
serious adverse event
SAP
Statistical Analysis Plan
SAS®
statistical software package from the SAS® Institute
SMQ
standardised MedDRA Query
SOC
system organ class
TEAE
treatment-emergent adverse event
VAS
visual analogue scale
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1
Objectives
The trial objectives and endpoints are summarized in Panel 1.
Panel 1
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
 To evaluate the efficacy of Lu AG09222 
for the prevention of migraine in 
participants with unsuccessful prior 
preventive treatments
Primary endpoint:
 Change from baseline in the number of monthly migraine days 
(MMDs) (Weeks 1 to 4)
Secondary endpoints:
 50% MMD response: ≥50% reduction from baseline in MMDs 
(Weeks 1 to 4)
 Change from baseline in the number of monthly headache days 
(MHDs) (Weeks 1 to 4)
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
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Objectives
Endpoints
Primary Objective (continued)
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
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Objectives
Endpoints
Safety Objective
 To evaluate the safety and tolerability of 
Lu AG09222
Safety Endpoints
- Adverse events 
- 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 ADAs including NAbs
- C-SSRS score 
2
Trial Design
This is an interventional, multi-national, multi-site, randomized, double-blind, parallel-group,
placebo-controlled Phase IIa trial designed to demonstrate proof-of-concept, that is, to 
investigate whether the inhibitory action of Lu AG09222 on the PACAP pathway can be an 
effective mechanism for migraine prevention.
The target population for this trial is defined as participants diagnosed with migraine as 
outlined in the International Classification of Headache Disorders Third Edition (ICHD-3) 
guidelines, with documented evidence of migraine occurring on 
 per month prior to 
screening, as confirmed via prospectively collected information in the electronic diary 
(eDiary) during the screening period and with documented evidence of failure of 2 to 4 
different preventive migraine medications in the past 10 years. Participants with a concurrent 
diagnosis of medication overuse headache (MOH) are allowed in the trial.
The aim is that approximately 30% of the randomized participants will have episodic 
migraine (EM; participants with headache occurring on <15 days). This will be ensured 
through a cap on the number of randomized EM participants.
 
A total of 230 participants, recruited from specialist settings, will be randomly allocated via a 
randomization system to one of three treatment groups: Lu AG09222 
 Lu AG09222 
, or placebo, in a ratio of 2:1:2.
Randomization will be stratified by region (North America versus Europe) and 
 
The total trial duration from the Screening Visit to the Safety Follow-up Visit is 
approximately 16 weeks and includes a Screening Period (28 to 30 days) and Safety Follow-
up period is 12 weeks (includes the 4 weeks Treatment Period).
Participants will receive the investigational medicinal product (IMP) in the form of a single-
dose administration at the Baseline Visit with either Lu AG09222 or placebo by intravenous 
(IV) infusion over 30 minutes (+15 minutes).
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Participants will complete a daily headache eDiary from the Screening Visit until the Safety 
Follow-up Visit or Efficacy Follow-up/Withdrawal Visit.
During the Baseline Visit, assessments of safety will be performed before and after the 
infusion. At this visit, adverse event details will be collected as well as safety laboratory test 
results, ECG results, weight, vital signs findings, and blood samples 
 
ADAs including NAbs, 
 
Participants must complete the eDiary recording of headaches that ended prior to infusion 
(i.e., for headaches not yet recorded in the eDiary).
Participants who complete the trial will attend a Safety Follow-up Visit at 8 weeks (Week 12)
after the Primary Outcome Visit.
Participants 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.
 
 
 
 
 
 
 
 
 
 
The trial design is presented in Panel 2 (including the trial periods) and the scheduled trial
procedures and assessments are summarized in Appendix II.
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Panel 2
Trial Design
IMP = investigational medicinal product.
The trial consists of a screening period (28 to 30 days), a treatment period (4 weeks), and a safety follow-up 
period (12 weeks after IMP administration). IMP (Lu AG09222 
, Lu AG09222 
, or placebo) 
will be administered by intravenous infusion at the Baseline Visit. At Week 4, participants will complete the 
Primary Outcome Visit and will return to the clinic 8 weeks later (12 weeks after IMP administration) for a 
Safety Follow-up Visit.
3
COVID-19
For this trial, all participants are considered to have been enrolled after the beginning of the 
COVID-19 outbreak.
The following information is collected with regards to COVID-19:

Whether a visit was done remotely due to COVID-19 including which assessments 
were/were not performed

If a visit was not done, whether it was not done due to COVID-19

Whether participants withdrew due to the COVID-19 situation

Whether participants got diagnosed with COVID-19 
The information collected with respect to COVID-19 will be presented in data listings. 
COVID-19 vaccinations are allowed provided the vaccinations have been completed for at 
least 14 days prior to the Screening Visit. Vaccinations during the trial are allowed providing 
the vaccination is received at least 3 days after the IMP administration. The vaccinations, 
including brand names, if used during the trial, will be reported as concomitant medications.
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4
Definitions
4.1
Definition of Baseline
For the endpoints based on daily recordings in the eDiary that are summarized in a monthly 
measure, the baseline value will be based upon the data recorded daily in the headache eDiary 
during the first 28 days following the Screening Visit.
For the endpoints based on daily recordings in the eDiary that are summarized in a weekly
measure is derived as the average of the weekly values of the 28-day screening period. 
For all other endpoints, the baseline assessment will be the latest available valid measurement 
taken prior to the administration of IMP.
4.2
Definition of Periods
The trial consists of the following periods:
•
Screening Period (28-30 days): Starts at the Screening Visit (Visit 1) and continues up 
to start of Visit 2 IMP infusion (Week 0).
•
Treatment Period (4 weeks): Starts at start of Visit 2 IMP (Week 0) infusion and 
continues up to and including Visit 4 (Week 4).
•
Safety Follow-up Period (12 weeks): Starts at start of Visit 2 IMP (Week 0) infusion 
and continues up to and including the Safety Follow-up visit (Week 12).
4.3
Definition of Withdrawal 
Participants who have received IMP infusion at Visit 2 and have withdrawn from the trial
prior to the Primary Outcome Visit (Week 4), will be described as withdrawn from trial. The 
complementary group will be described as completed the trial.
4.4
Definition of Planned versus Actual Treatment
Participants will receive a single IV infusion of 
 Lu AG09222, or 
 Lu 
AG09222 or Placebo.
Planned treatment is defined as the treatment a participant was randomized to. 
Actual treatment is defined as the treatment a participant actually received during the trial.
For reporting purposes, the following will be summarized by planned treatment:

Efficacy

Demographics and baseline characteristics

Disposition

eDiary compliance

Concomitant medication
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And the following will be summarized by actual treatment:

Adverse events

Exposure

Immunogenicity

Laboratory parameters, vital signs, ECG, and C-SSRS
Unless otherwise specified, data listings will display actual treatment. 
4.5 Definition of Region
The following countries are included in the regions:

North America: United States of America

Europe: Czech Republic, Georgia, Denmark, Slovakia, Poland
4.6
Definitions for 
 Migraine 
Day, Headache Day, 
Participants will complete an eDiary, from the Screening Visit until the Safety Follow-up 
Visit or Efficacy Follow-up/Withdrawal Visit. In the headache diary, participants collect daily 
information on key symptoms and characteristics as mentioned in the definition of migraine 
(see section 4.6.2). For each day, the participant will record if they experienced any 
headaches. For each experienced headache, the start and stop date and time will be collected. 
The participant will record further daily information regarding headache characteristics (for 
instance, headache severity, additional symptoms) 
 
 Headache items will be assessed with a yes/no response; and severity will be 
rated as mild, moderate, or severe. Participants are expected to complete the eDiary on a daily 
basis during the trial regardless of whether they experienced a headache on that day.
 
The eDiary-reported headache characteristics will be used in derivations of efficacy 
endpoints, including rules for handling missing data, as described in section 22.1.1.
For the purpose of endpoint derivations, 
 
 and migraine and headache days are defined as described below.
4.6.1
 
 
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4.6.2
Migraine Day 
A migraine day is defined as a day with a headache that meets following criteria listed below:
1. A headache that:
Lasted 4 hours or more and had at least 2 of the following:
1. Unilateral location
2. Pulsating quality
3. Moderate or severe pain intensity
4. Aggravation by or causing avoidance of routine physical activity
and had at least 1 of the following:
1. Nausea and/or vomiting
2. Photophobia and phonophobia
2. Or A headache that lasted 30 minutes or more and the participant had an aura with the 
headache (migraine with aura*)
3. Or A headache that lasted 30 minutes or more and meets 2 of the 3 following criteria
(probable migraine**):

Lasted 4 hours or more

Had at least 2 of the following:
1. Unilateral location
2. Pulsating quality
3. Moderate or severe pain intensity
4. Aggravation by or causing avoidance of routine physical activity

Had at least 1 of the following:
1. Nausea and/ or vomiting
2. Photophobia and phonophobia
4. Or a day with a headache that is successfully treated with a triptan, ergotamine, or other 
migraine-specific acute medication 
 
If a headache lasts ≥72 hours, the days will still be counted as headache days or migraine 
days as aligned with the IHS guidelines. 
A day where the symptoms are not recorded for an ongoing headache (missed data entry) will 
be classified as a headache day.
Further details on the definitions:
 
 
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4.6.3
Headache Day
A Headache Day is defined as a day with a headache that lasts ≥30 minutes or that meets the 
definition of a Migraine Day (see section 4.6.2).
4.6.4
 
 
 
 
 
4.6.5
 
4.6.6
 
 
 
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5 Analysis Sets
The following analysis sets will be used to analyse and present the data:
•
all-participants-enrolled set (APES) – all screened participants
•
all-participants-randomized set (APRS) – all randomized participants
•
all-participants-treated set (APTS) – all participants in the APRS who received an 
infusion of IMP
•
full-analysis set (FAS) – all participants in the APTS who have a valid baseline 
assessment of the number of MMDs and a valid assessment of MMDs over Weeks 1 
to 4.
•
full-analysis set long term (FAS-LT) – all participants in the APTS who have a valid 
baseline assessment of the number of MMDs and at least one valid post-baseline 
assessment of MMDs (Weeks 1 to 4 or Weeks 5 to 8 or Weeks 9 to 12)
The participants and data will be classified into the analysis sets according to these definitions 
at a Classification Meeting held after the trial database has been released, but before the blind 
has been broken.
The presentation and analyses of the primary endpoint, the secondary endpoint (50% MMD 
response) and safety tables (including exposure, concomitant medications and 
immunogenicity) will be based on APTS (see section 21.3).
 
 
6
Descriptive Statistics
Unless otherwise specified, summary statistics (n, arithmetic mean, standard deviation [SD], 
median, lower and upper quartiles, minimum and maximum values) will be presented for 
continuous variables, and counts and, if relevant, percentages will be presented for categorical 
variables.
Unless otherwise specified, data listings include site, treatment group, participant screening 
number, sex, age, race, baseline weight, BMI and
 
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7
Participant Disposition
7.1
Summary of Participant Disposition
Participant disposition will be summarized by treatment group and include the number of 
participants in each analysis set defined in section 5, and the number of participants in the 
APTS who completed or withdrew from trial.
If any visits are changed from clinic to remote, a table will be provided presenting by type of 
visit (on clinic or remote) and treatment group.
7.2
Withdrawals
The number of participants who withdraw from the trial will be summarized by treatment 
group. The primary reason for withdrawal will be presented, as well as all reasons for 
withdrawal.
Participants who withdrew from the trial will be listed and the listing will include the number 
of days in the trial until withdrawal from the trial, the number of days on IMP, the primary 
reason for withdrawal, all reasons for withdrawal, and a flag if the drug code was broken.
Kaplan-Meier failure plots of time to withdrawal will be presented by treatment group. The 
time will be calculated from the date of IMP to the date of withdrawal in the Treatment 
Period. Participants who complete the Treatment Period will be regarded as censored at the 
End of Week 4 visit (Visit 4). 
All tables, graphs, and listings will be based on the APTS.
8
Demographics and Baseline Characteristics
Demographics (sex, age, age group, race and region); baseline characteristics (height, weight, 
and BMI); baseline disease characteristics; and baseline efficacy variables will be summarized
by treatment group.
All the demographics and baseline characteristics data described below will be summarized 
based on the APTS.
The baseline disease characteristics comprise of:

age and age group (≤ 21 years, > 21 years) at first diagnosis of migraine

time since first migraine ICHD-3 diagnosis (years)

time since first migraine diagnosis group (≤ 15 years, > 15 years)

current type of migraine (CM or EM)

time since current migraine ICHD-3 diagnosis (years)
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o

has an MOH diagnosis (yes/no)

for women: whether migraines started before or after menarche 

for men: whether migraines started before or after puberty 

whether the start of migraine was related to any event
The eDiary reported baseline headache and migraine characteristics (data collected on daily 
basis during the screening period) that will be summarized are:

number of baseline MMDs 

number of baseline MHDs

 
 
)
 
 
 
 
Concurrent as well as relevant past medical, neurological, and psychiatric disorders will be 
coded using the MedDRA, Version 25.0 (or later) and summarized by treatment group. 
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A concurrent medical, neurological, or psychiatric disorder is a disorder that is ongoing at the 
Screening Visit. A past medical, neurological, or psychiatric disorder is a disorder that ended 
prior to the Screening Visit. Social history will be summarized by treatment group.
Summaries of prior preventive treatment failure medications within 10 years prior to the 
Screening Visit will be presented by treatment group. The number and percentage of 
participants with each type of prior treatment failure (lack of efficacy, safety/tolerability, or 
contraindication) will also be presented by treatment group, as well as the number of prior 
preventive treatment failures.
9
Recent and Concomitant Medication
Recent and concomitant medication will be coded using the WHO Drug Dictionary
(WHO-DDE, version March 2022 or later).
Medications will be classified according to the start and stop time and summarized by 
anatomical therapeutic chemical (ATC) code, generic drug name and treatment group. 
Handling of missing or incomplete dates is specified in section 22.3.4.
The following categories will be used:

Prior medications: Medications with a stop date before IMP infusion

Concomitant medication: continued after IMP infusion or started at or after IMP 
infusion
The tables for prior and concomitant medications will be based on the APTS.
 
 
All disallowed medications entered in the eCRF, which will be identified via a clinical review 
of the coded medication data in the eCRF, will be listed based on the APRS. The listing will 
include the generic drug name, the duration, the start and end dates, and dosing information. 
 
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10 Exposure 
For the IMP Visit, information related to infusion completed as planned in full (yes/no), 
infusion temporarily interrupted (yes/no), and infusion lasted longer than 30 (+15) minutes 
(yes/no), as well as descriptive statistics for the duration of infusion (this duration includes 
duration of any infusion interruptions), and duration of temporary interruptions will be 
summarized by actual treatment group.
The summaries will be based on the APTS. All infusion data will be listed. 
11
 
 
12 Efficacy
12.1
General Efficacy Analysis Methodology
For the primary and the secondary endpoint concerning MMDs, the efficacy analyses will be 
based on the APTS. The analyses of the remaining efficacy endpoints with a single post-
baseline timepoint will be based on the FAS, while the efficacy endpoints with multiple post-
baseline timepoints will be based on the FAS-LT.
All the tables and graphs will be presented by treatment group.
For primary and secondary endpoints, statistical tests for comparisons of the 
 and 
 
 dose of Lu AG09222 versus placebo, will be reported with one-sided p-values and two-
sided 90% confidence intervals.
In addition to the above, for primary, secondary, and all exploratory efficacy endpoints, two-
sided 95% confidence intervals and p-values for the comparisons of the 
 and 
 
dose of Lu AG09222 versus placebo will be reported.
All two-sided p-values are considered descriptive p-values.
The derivation of the endpoints is described in section 22.1. 
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12.2
Testing Strategy
The type 1 error will only be controlled for the primary analysis comparing the primary 
endpoint (the change from baseline in MMDs [Weeks 1 to 4]) for the 
 Lu AG09222 
dose versus 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.
12.3
Analysis Methodology for the Primary Endpoint
12.3.1
Primary Estimand
The primary estimand 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.
The following intercurrent events (ICEs) will be addressed:

Use of acute migraine-specific medication

Use of preventive migraine therapy 

Use of non-migraine specific medication

IMP not administered per protocol

COVID-19 Vaccination during the Treatment Period – Treatment Policy Strategy
The attributes of the primary estimand are:

The treatment condition of interest is the comparison of 
 Lu AG09222 to 
placebo without use of preventive migraine medication.

The population of interest are participants with a diagnosis of migraine, with 
migraine occurring on
per month and headache occurring on ≤26 days.

The endpoint to be considered is the change from baseline in MMDs (Weeks 1-4)

The population level summary will be mean difference in the primary endpoint, 
comparing the effect of 
 Lu AG09222 to placebo.
Intercurrent events:

use of acute migraine-specific medication implicitly a composite strategy is applied 
since the definition of the MMDs based on the ICHD-3 guideline includes the impact 
of the use of acute migraine-specific medication on whether a day is considered a 
migraine day

use of acute non-migraine specific medication, that is reported to have successfully 
treated the headache will be addressed using a treatment policy strategy.

use of preventive migraine therapy will be addressed using a hypothetical strategy, 
where data collected after preventive medication intake is considered missing and are 
handled using missing data analysis methods (see section 22.1.3)

infusion interruptions or termination before full dose is received will be addressed 
using a treatment policy strategy.
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12.3.2
Strategies for Addressing Intercurrent Events in Primary Estimand
Use of Acute Migraine-Specific Medication – Composite Strategy
A composite strategy will be applied to address the use of acute medication: if acute migraine-
specific medication (
) is used during a day, and is reported to have 
successfully treated the headache, this day counts as a migraine day. See section 4.6.2 for the 
definitions of a Migraine Day during the Screening Period. The same definitions will be used 
for the Treatment Period. The eDiary data collected are used regardless of these intercurrent 
events.
For presentation of this intercurrent event, see section 9.
Use of Preventive Migraine Treatment – Hypothetical Strategy
A hypothetical strategy will be applied to address the use of preventive migraine treatment by 
setting the eDiary data collected after the use of preventive medication as missing and 
applying multiple imputation where, for the missing observations, information is borrowed 
from non-missing observations from the same treatment group.
For presentation of this intercurrent event, see section 9.
Use of Non-migraine Specific Medication – Treatment Policy Strategy
A treatment policy strategy is used to address the intercurrent event of use non-migraine 
specific medication, that is reported to have successfully treated the headache in which the 
eDiary data collected are used regardless of these intercurrent events.
IMP not Administered per Protocol – Treatment Policy Strategy
Infusions not completed as planned, infusions temporarily interrupted, and infusions that 
lasted longer than 30 (+15) minutes could impact the efficacy. These intercurrent events will 
be addressed using a treatment policy strategy, in which the eDiary data collected are used 
regardless of these intercurrent events.
For presentation of these intercurrent events, see section 10.
COVID-19 Vaccination During the Treatment Period – Treatment Policy Strategy
A treatment policy strategy is used to address the intercurrent event of getting COVID-19 
vaccination during the Treatment Period, in which the eDiary data collected are used 
regardless of these intercurrent events.
12.3.3
Primary Analysis of the Primary Endpoint
The main estimator for the primary estimand is defined as the least squares mean difference 
for the mean change from baseline in the number of MMDs over Weeks 1 to 4 between 
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 Lu AG09222 versus the placebo group, obtained from an ANCOVA with baseline 
MMDs as a covariate and treatment (placebo, 
 Lu AG09222, 
 Lu AG09222), 
population (EM, CM), and 
 
Missing data for the MMD over Weeks 1 to 4 (
) will be 
addressed by using Multiple Imputation performed in which the remaining missing data will 
be imputed using a sequential regression-based multiple imputation method, based on the 
imputation models established from the corresponding randomized treatment group.1
200 simulations will be performed to generate the datasets that will be analysed using the 
specified ANCOVA model above. These analyses will be combined using Rubin’s rule to 
form a unique point estimate and standard error, taking into account the uncertainty of the 
imputation.2 The combined least square means difference between 
 Lu AG09222 and
the placebo group will be evaluated at a one-sided 5% significance level and constitutes the 
primary analysis.
The SAS® code for this analysis is shown in Appendix IV.
The analysis will be performed for the first month of the trial, derived as specified in section 
22.1.1. The term “month” refers to 4-week periods.
This analysis will include all participants in the APTS.
12.3.4
Rationale for Selected Analysis Method for the Primary Endpoint
The MMDs are considered continuous data, and they are analysed using methods based on 
observations following a normal distribution. An ANCOVA analysis has been chosen for the 
primary analysis. Covariates are included in the model based on an approach that includes key 
factors to represent trial design, namely treatment group,
 
baseline MMD and migraine population (EM, CM) to adjust for baseline differences in 
disease characteristics.
12.3.5
Sensitivity Analyses of the Primary Endpoint
The following sensitivity analyses will be conducted on the APTS:

 
 
 
 

Assessing the impact of missing data using placebo-based multiple imputation (pMI): 
An analysis will be performed using pattern-mixture model (PMM), in which the 
 missing data
 will be imputed using a regression-based multiple imputation method, based 
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on the imputation models established from the placebo group. 200 simulations will be 
performed to generate the datasets that will be analysed using the model described in 
section 12.3.3.These analyses will be combined using Rubin’s rule to form a unique 
point estimate and standard error, taking into account the uncertainty of the 
imputation. The SAS® code for this sensitivity analysis is shown in Appendix IV.
12.3.6
 
 
12.4
Analysis Methodology for the Secondary Endpoints
The following endpoints will be analysed:

50% MMD response: ≥50% reduction from baseline in MMDs (Weeks 1 to 4)

change from baseline in the number of MHDs (Weeks 1 to 4)
For 50% MMD response, the estimand strategy will be the same as for the primary analysis 
(see section 12.3.1), except that the population level summary will be the odds ratio 
comparing Lu AG09222 
 and Lu AG09222 
 to placebo from a logistic 
regression model with baseline MMDs as covariate and treatment, population (EM, CM), 
 
as fixed factor.
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The logistic regression model will be fitted using the ML method and the logit link function.
In case of convergence issues, the Firth’s bias-reducing penalized likelihood method will be 
applied.
The 200 simulated datasets from the primary analyses (section 12.3.3) will be dichotomized 
into responders ( ≥50% reduction of MMDs) and non-responders. Each of the dichotomized 
datasets will be analysed using the logistic regression model specified above. For each 
analysis the results will then be transformed into a test statistic, which is approximately 
standard normally distributed under the null hypothesis of no treatment effect, following the 
approach by Ratitch et al,.3 The transformed statistics will be combined across the 200 data 
sets, using PROC MIANALYZE to generate a combined set of estimates, test statistics and p-
value for these tests. The SAS® code for this analysis is shown in Appendix IV.
The combined odds ratios for Lu AG09222 
 and 
 compared to placebo will be 
presented with one-sided p-values and 90% CIs. In addition, the differences in the combined
response rates for Lu AG09222 
 and 
 versus placebo will be presented. 
The analysis will be based on the APTS.
For the secondary endpoint, change from baseline in the number of MHDs (Weeks 1 to 4), the 
estimand strategy will be the same as for the primary analysis (see section 12.3.1). 
The endpoint will be analysed with an ANCOVA with baseline MHDs as a covariate and 
treatment (placebo, 
 Lu AG09222, 
 Lu AG09222), population (EM, CM), 
 
 as fixed factor.
The analysis will be based on the FAS.
12.5
 
 
 
 
 
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13 Safety
13.1
Adverse Events
13.1.1
General Methodology for Adverse Events
Unless otherwise specified, tables, graphs, and listings will be based on the APTS.
All the tables and graphs will be presented by treatment group.
Tables by preferred term and tables by system organ class (SOC) and preferred term will be 
sorted in descending order based on the percentages of participants with these adverse events 
in the Lu AG09222 
 group.
Unless otherwise specified, the summaries of adverse events will include the number and 
percentage of participants with an adverse event and number of events. In tables displaying 
SOC or preferred terms, participants are counted only once within each SOC or preferred 
term.
Listings of adverse events will be sorted by site, treatment group, participant screening 
number, preferred term, verbatim, adverse event start date, adverse event stop date, the date of 
IMP infusion, the time since IMP infusion, duration of the adverse event, date of death, action 
taken, causality, intensity, seriousness, and outcome. 
For adverse events that change in intensity, each intensity will be included. In listings of 
adverse events, start or stop dates will be displayed as collected also in case of partially or 
completely missing dates. 
13.1.2
Coding of Adverse Events
Adverse events will be coded using MedDRA, Version 25.0 or later.
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13.1.3
Classification of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:

pre-treatment adverse event – an adverse event that starts on or after the date the 
participant signed the Informed Consent Form and prior to the date and time of the 
dose of IMP.

treatment-emergent adverse event (TEAE) – an adverse event that starts during or 
after administration of the dose of IMP, or a pre-treatment adverse event that increases 
in intensity or becomes serious during or after administration of the dose of IMP.
For handling of adverse events with incomplete start dates to facilitate this classification, see 
section 22.3.5. Note that adverse events with incomplete start dates will be classified as 
treatment-emergent simply if the imputed start date is on or after the date of IMP infusion, 
since the start time of the adverse event will not be imputed, unless the investigator in such a 
case has assessed that the causality to IMP is not related - prior to IMP.
An adverse event is considered causally related to the use of the IMP when the causality 
assessment by the investigator is probable or possible. If the causality assessment is missing, 
the adverse event is considered possibly causally related.
13.1.4
Presentation of Adverse Events
All adverse events will be listed for the APRS, including a flag for TEAEs.
An overview of the numbers and percentages of participants with TEAEs, serious adverse 
events (SAEs), TEAEs leading to infusion interruption, TEAEs leading to withdrawal, and of 
participants who died will be provided based on the APTS. For TEAEs, SAEs, and TEAEs 
leading to withdrawal, the total number of events will be included.
All pre-treatment adverse events will be summarized and listed for the APRS, separately.
13.1.5
Presentation of Treatment-emergent Adverse Events
The following summaries will be provided for the APTS:

TEAEs by SOC and preferred term

TEAEs by preferred term

TEAEs by sex and preferred term

TEAEs with an incidence ≥2% and 5% in any treatment group by preferred term

causally related TEAEs by SOC and preferred term

TEAEs by severity (mild/moderate/severe), SOC, and preferred term

causally related TEAEs by severity, SOC, and preferred term

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For TEAEs occurring on the day of dosing after infusion start, TEAEs with missing start 
times will also be included.
13.1.6
Presentation of Deaths
All the adverse events in participants who died will be listed for the APRS.
13.1.7
Presentation of Serious Adverse Events
All the SAEs will be listed for the APRS.
Treatment-emergent SAEs for the APTS will be summarized by:

SOC and preferred term

preferred term
13.1.8
Presentation of Adverse Events Leading to Withdrawal
All the adverse events leading to withdrawal will be listed for the APRS.
TEAEs leading to withdrawal will be summarized by:

SOC and preferred term

preferred term
13.1.9
Presentation of Adverse Events Leading to IMP Infusion Interruption
All the adverse events leading to IMP infusion interruption will be listed for the APRS.
TEAEs leading to IMP infusion interruption will be summarized based on APTS by:

SOC and preferred term

preferred term
13.1.10
 
 
13.2
General Methodology for Other Safety Data
Unless otherwise specified, tables, graphs, and listings will be based on the APTS.
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All the tables will be presented by treatment group.
The denominators for the summaries of a given variable will be based on the number of 
participants with non-missing values at a given visit or during the assessment period.
Descriptive statistics for the safety variables, both absolute values and changes from baseline, 
will be presented by visit. 
The number and percentage of participants with at least one PCS value at any post-baseline 
assessment time point will be summarized by variable. All available assessments will be 
included in the evaluation of PCS values. 
The number and percentage of participants with values out-of-reference range and/or PCS 
range will be summarized by variable, visit, and last post-baseline assessment.
For participants with post-baseline PCS values, listings will be provided including all the 
values for those participants for the variable, with flagging of PCS values and out-of-
reference-range values.
All the adverse events occurring in participants with post-baseline PCS values will be listed 
by treatment group and participant screening number; the listing will include the PCS value, 
the assessment date, the change from baseline in PCS value, the preferred term for the adverse 
event, and the start date and stop date of the adverse event. The PCS values and adverse 
events will be listed in chronological order according to assessment date and the start date of 
the adverse event.
13.3
Clinical Safety Laboratory Test Data
13.3.1
Data Presentation
The PCS criteria for the clinical safety laboratory tests are in Table 2.
The clinical safety laboratory test values will be presented in Système International (SI) units.
Fasting lipid and fasting glucose concentrations will be presented in separate tables from the 
overall laboratory tables.
For urine dipsticks, for which the results are categorical values (for example, negative, trace, 
1+, 2+), the number and percentage of participants will be summarized by visit for each test. 
The microscopy results will be listed by assessment time point for participants with findings.
13.3.2
Anti-drug Antibody Including Neutralizing Antibody Assessments
Analysis of specific anti-Lu AG09222 antibodies is restricted to participants in the APTS who 
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For participants with pre-existing antibodies at Baseline, the number and percentage of 
participants who are positive for anti-Lu AG09222 antibody will be summarized. In addition, 
the number and percentage of participants who develop anti-drug antibodies to Lu AG09222 
during the trial will be summarized at each scheduled visit. Denominators for percentages will 
be the total number of samples taken for the specified visit. For participants with ADA, 
neutralizing properties of anti-Lu AG09222 antibodies will also be summarized.
Participants with a positive anti-Lu AG09222 antibody result will be listed.
All the adverse events occurring in participants with positive anti- Lu AG09222 antibody or 
with pre-existing antibodies at Baseline, will be listed. The listing will include the ADA 
result, the assessment date, the preferred term for the adverse event, and start date and stop 
date of the adverse event. The ADA results and adverse events will be listed in chronological 
order according to assessment date and the start date of the adverse event.
In addition, summaries of TEAEs by SOC and preferred term, summaries for TEAEs included 
in the SMQ Hypersensitivity Narrow by SOC and preferred term will be provided for 
participants who are ADA-positive and ADA-negative separately.
Furthermore, the potential impact of ADA on efficacy will be explored by providing
summaries of change from baseline in monthly migraine days for participants who are ADA-
positive and ADA-negative separately.
13.3.3
Potential Drug-induced Liver Injury (DILI)
Signals of DILI will be assessed according to the FDA guideline4 using the following criteria:

ALT or AST >2×, >3×, >5×, >10×, or >20×ULN

total bilirubin (BILI) >2×ULN

alkaline phosphatase (ALP) >1.5×ULN

ALT or AST >3×ULN AND total bilirubin >1.5× or >2×ULN
Participants fulfilling any of the criteria will be listed, and the listing will include all the ALT, 
AST, BILI, and ALP values for those participants, sorted by assessment date and time in 
ascending order. If a criterion for a test is fulfilled, the value will be flagged with the highest 
criterion fulfilled (for example, AST >3×ULN, >5×ULN, >10×ULN, or >20×ULN).
In addition, assessment time points for participants for whom Hy’s Law is potentially fulfilled 
will also be flagged in the listings (pHYL):

ALT or AST >3×ULN AND

alkaline phosphatase <2×ULN AND

total bilirubin ≥2×ULN
The number of participants who met any of the criteria specified above at any post-baseline 
visit will be summarized. In the summaries, each participant will be counted only once using 
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also include the number of potential Hy’s Law cases. If any participants fulfil Hy’s Law (all 3 
criteria fulfilled), information collected related to this finding will be presented in data 
listings.
13.4
Vital Signs and Weight
The PCS criteria used for vital signs and weight are the Lundbeck standard PCS criteria
shown in Table 3.
13.5
ECGs
The PCS criteria used for the ECG parameters are the Lundbeck standard PCS criteria 
described in Table 4.
In addition to the tables and listings specified in section 13.2, the absolute values and changes 
from Baseline in QTcF will also be summarized categorically by visit and treatment. The 
categories that will be used are as follows for the absolute QTcF values:

QTcF interval < 450 msec

QTcF interval 450 - 480 msec

QTcF interval > 480 - 500 msec

QTcF interval > 500 msec
The categories that will be used for the change from baseline QTcF values are:

QTcF interval increase from baseline > 30 msec

QTcF interval increase from baseline > 60 msec
Furthermore, the number and percentage of participants being classified as having either a 
normal, abnormal but not clinically significant, or abnormal and clinically significant ECG 
result based on the overall interpretation of the ECG from the investigator will be summarized 
by visit and treatment group.
13.6
Other Safety Endpoints
13.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores
The C-SSRS was administered:
for lifetime (using the Baseline/Screening Version) – the C-SSRS assessment at 
screening that collects a lifetime recall
for the past 12 months at screening (using the Baseline/Screening Version) – the C-
SSRS assessment at screening that focuses on the last 12 months
at baseline (using the Since Last Visit Version) – the C-SSRS assessment at baseline that 
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 post-baseline (using the Since Last Visit Version) – the C-SSRS assessments after 
baseline
The numbers and percentages of participants with lifetime, past 12 months, baseline, or post-
baseline suicide-related events based on the C-SSRS will be summarized by treatment group. 
For each summary, the most severe item with an answer “Yes” for each participant according 
to the ordering given in Panel 6 is displayed. For the post-baseline assessments, the 
summaries will be by treatment group and period and the most severe item with an answer 
“Yes” for the whole period for each participant related to suicidal ideation and/or behaviour 
will be summarized.
The number and percentage of participants with no suicidal ideation or behaviour will be
included in the summaries.
Panel 6
C-SSRS Scores
C-SSRS Score
Related to:
1
Wish to be dead
Suicidal ideation
2
Non-specific active suicidal thoughts
3
Active suicidal ideation with any methods (not plan) without intent to act
4
Active suicidal ideation with some intent to act, without specific plan
5
Active suicidal ideation with specific plan and intent
6
Preparatory acts or behaviour
Suicidal behaviour
7
Aborted attempt
8
Interrupted attempt
9
Non-fatal suicide attempt
10
Completed suicide (only applicable for the post-baseline assessments)
The C-SSRS scores will be summarized by visit based on the APTS for participants with at 
least one post-baseline C-SSRS assessment, regardless of whether they had a baseline 
C-SSRS assessment.
Missing C-SSRS scores will not be imputed.
Positive responses to non-suicidal self-injurious behaviour will be summarized separately.
For participants with any post-baseline suicidal behaviour (C-SSRS scores of 6 to 10), listings 
will be provided including all C-SSRS scores for those participants; C-SSRS scores related to 
suicidal behaviour will be flagged.
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15 Pharmacokinetic/Pharmacodynamic Analyses
 
 
16
 
 
 
 
17 Blinded Data Reviews
The quality of the trial will be overseen by performing blinded data reviews during the 
conduct of the trial. The reviews may include, but are not limited to, data quality, protocol 
adherence, and the appropriateness of design assumptions, including the sample size 
assumptions. 
An independent Safety Data Monitoring Committee (DMC) will regularly monitor the 
participants' safety data according to the DMC Charter. The DMC will have access to 
unblinded information for the double-blind treatment for each participant. Members of the 
DMC will not be involved in other trial-related tasks.
18 Interim Analyses
No interim analyses are planned.
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19 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 and allowing for stopping for futility. A population with 30% EM and 70% 
CM participants 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 participants 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% withdrawal 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.
20 Statistical Software
The statistical software used will be SAS®, Version 9.4 or later.
21
21.1
 
 
 
 
 
 
 
 
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21.2
 
 
 
 
 
21.3
 
 
 
21.4
 
 
 
 
 
 
 
 
21.5
 
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21.6
 
 
 
 
 
 
 
 
 
 
 
 
 
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22 Details on Data Handling
22.1
Derived Variables
22.1.1
eDiary
22.1.1.1
Determination of Migraine Days and Headache Days
Headache day:

A day is considered a headache day if a headache (as identified through a unique 
headache ID) has been reported to take place on that day with a duration of at least 30 
minutes on that day, or if the day is a migraine day.

A day is considered a non-headache day if one or more headaches (as identified 
through a unique headache ID) have been reported to take place on that day, but none 
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of them make the day qualify as a headache day as defined above. Or no headaches 
have been reported to take place on that day, but the headache diary was completed on 
that day, confirming that the participant did not have a headache to report.

A day is considered a missing observation for headache day, if it is not a headache day 
or a non-headache day, as defined above.
Migraine day:

A day is considered a migraine day if a headache (as identified through a unique 
headache ID) has been reported to take place on that day and fulfils the criteria for a 
migraine on that day (based on the criteria specified in section 4.6.2).

A day is considered a non-migraine day if one or more headaches (as identified 
through a unique headache ID) have been reported to take place on that day and 
headache characteristics have been reported for all headaches on that day, but none of 
them make the day qualify as a migraine day as defined above. Or no headaches have 
been reported to take place on that day, but the headache diary was completed on that 
day, confirming that the participant did not have a headache to report.

A day is considered a missing observation for migraine day, if information (e.g. 
headache characteristics) is missing in the headache diary to be able to classify the day 
as a migraine day or a non-migraine day. 
If characteristics/symptoms for the same headache (identical headache ID) are reported more 
than once within the same day, then that day is considered a migraine day, if at least one set of
characteristics make the day qualify as such.
22.1.1.2
Monthly Migraine Days,
The following describes the derivation of MMDs. 
For a given headache, determine whether it is a migraine attack as defined in section 4.6.4. If 
that is the case, then each day of the headache with a headache duration of at least 30 minutes 
or where the day itself fulfils the Migraine Day definition in section 4.6.2 is considered a 
migraine day according to Derivation method 1.
 
 
 
 
 
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4-Week Intervals
4-week intervals are considered for the following endpoints:

change from Baseline in the number of MMDs (Weeks 1 to 4)

change from Baseline in the number of MMDs (Weeks 5 to 8)

change from Baseline in the number of MMDs (Weeks 9 to 12)
For Baseline and each 4-week period post-baseline, the MMDs/MHDs will be derived as the 
number of migraine days within each 28-day interval using the imputation rules described 
below. The following 4-week periods post-baseline are considered: Weeks 1 to 4, Weeks 5 to 
8 and Weeks 9 to 12.
 
 
 
 
 
 
 
 
 
 
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22.1.1.3
Migraine/
 Response Variables
The following describes the derivation for response for monthly migraine/
 days.
The following response variables will be derived: 50%, 
 A responder is 
defined as a participant who achieves a ≥50%, 
 reduction in 
MMDs
 respectively, compared to the baseline MMDs
 The derivation of these 
response endpoints will be based on the MMD
 
For each 4-week interval after IMP dosing, the response status of a participant will be derived 
based on the percentage change from baseline in MMDs
. If the MMDs 
 value 
is missing for the 4-week interval in question, the response status will also be missing.
22.1.1.4
 
 
 
 
22.1.1.5
 
 
 
 
 
 
 
22.1.1.6
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
 
 
 
 
 
 
 
 
22.1.1.7
 
 
 
 
 
22.1.1.8
 
 
 
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
 
 
 
 
 
22.1.2
22.1.2.1
 
 
 
 
22.1.2.2
 
 
 
 
22.1.2.3
 
 
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22.1.2.4
 
 
 
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22.1.2.9
 
 
 
 
22.1.3
Handling of Data After ICE “Use of Preventive Therapy”
In the case of the intercurrent event “use of preventive therapy” occurs (see section 12.3.2), 
the data collected after preventive medication intake will be disregarded and set to missing.
22.2
Assigning Data to Visits
See section 4.1 for definition of Baseline values.
22.2.1
Safety Variables
Laboratory Tests, Vital Signs, Body Weight, ECG and C-SSRS
Assessments at unscheduled visits and withdrawal visits will be assigned to a nominal visit,
according to the visit windowing specified in Panel 6. Assessments for participants not 
receiving an infusion of IMP will be assigned to Visit 2 (Baseline).
Panel 6
Visit Windows - Laboratory Tests, Vital Signs, Body Weight, ECG 
and C-SSRS
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
V1 (Screening Visit)
-4
-28
Day -28 and before IMP 
infusion
V2 (Baseline Visit)
0
0
Same day as IMP infusion 
(Day 0) and prior to IMP 
infusion on that date
V3
2
14
After start of IMP infusion 
to Day 21
V4
4
28
Day 22 to Day 41 after 
start of IMP infusion
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Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
V5
8
56
Day 42 to Day 69 after 
start of IMP infusion
V6
12
84
Day 70 to Day 98 after 
start of IMP infusion
If there is more than one assessment at a visit (either due to multiple assessments or because 
an unscheduled or withdrawal visit assessment is mapped to a nominal visit with an already 
existing value) the value that will be used in summary tables by visit will be the one closest to 
the nominal day for the visit but prioritizing values from scheduled visits above values from 
withdrawal or unscheduled visits. In the ordering of multiple values, assessments without 
recorded time will come after assessments with recorded time and the first in the ordering will 
be selected. 
22.3
Handling Missing or Incomplete Dates/Times
22.3.1
Missing Headache End Date and Time
If the end date and time for a headache recorded in the eDiary is missing, the headache end 
date and time will be imputed with the end of trial date.
Note that for each participant, it is only possible to have a missing end date and time for the 
last headache entered, since a participant needs to complete a headache entry in order to 
report a new headache in the headache eDiary.
22.3.2
Withdrawal Date
Missing withdrawal dates will not be imputed and time to withdrawal from treatment will not 
be calculated for missing withdrawal dates.
22.3.3
Medical Disorder Start and Stop Dates
Incomplete dates will not be imputed. Classification of events into concurrent medical 
disorders or past disorders will be based on the reported ongoing status.
22.3.4
Medication Start and Stop Dates
Imputation of incomplete or partially missing dates will be performed in order to document 
the assigned categories specified in section 9.
The algorithm for imputing the start dates will follow the one used for imputing adverse event 
start dates, see section 22.3.5.


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For imputing stop dates, the following will apply, where UK and UKN indicate unknown or 
missing day and month, respectively:

UK-MMM-YYYY: Medication end date is imputed with the last day of the month

UK-UKN-YYYY: Medication end date is imputed with 31-DEC-YYYY
Medications marked as ongoing are considered concomitant medications.
22.3.5
Adverse Event Start and Stop Dates
Imputation of partially or completely missing dates will be included in the data to document 
the treatment-emergent status of the adverse event and assignment of the adverse event to a 
reporting period. For an adverse event with an imputed start date, the classification of the 
event as treatment-emergent will depend only on whether the imputed date is the same as the 
date of infusion and not the timepoint of the infusion, since start times for adverse events will 
not be imputed. No duration will be calculated for adverse events with incomplete start-or-
stop dates or for ongoing adverse events.
Imputation will follow the algorithm below. If an imputed start date after this procedure is 
after the end date, the start date will be set to the end date. 
Start Dates
Participants With No IMP Infusion
For participants who have not been treated, the imputation of the adverse event start date will 
be performed as follows, where UK and UKN indicate unknown or missing day and month, 
respectively:

UK-MMM-YYYY: The start date will be imputed with either the first day of the 
month or the date of Visit 1. The date of Visit 1 will be used if that is the later of the 
two and if it is within the specified month and year

UK-UKN-YYYY: The start date will be imputed with either JAN 1 or the date of 
Visit 1. The date of Visit 1 will be used if it is within the specified year.
If the adverse event start date is completely missing, it will be set equal to the date of Visit 1.
Participants Who Received an IMP Infusion
For participants who have been treated, the imputation of adverse event start dates will be 
performed as follows:
UK-MMM-YYYY:
If the year and month are equal to the year and month of treatment start date, the 
adverse event start date is imputed with the date of the dosing of IMP


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If the year is equal to the year of treatment start date: If the month is prior to the 
treatment start date, the adverse event start date is imputed with the last day of the 
month. If the month is equal to the month of the treatment start date, see above. If the 
month is after the month of the treatment start date, the adverse event start date is 
imputed with the first day of the month
If the year is prior to treatment start date, the adverse event start date is imputed with the 
last day of the month
If the year is after the year of treatment start date, the adverse event start date is imputed 
with the first day of the month
UK-UKN-YYYY:
If the year is equal to the year of treatment start date, the adverse event start date is 
imputed with treatment start date
If the year is prior to the year of treatment start date, the adverse event start date is 
imputed with 31-DEC-YYYY
If the year is after the year of treatment start date, the adverse event start date is imputed 
with 01-JAN-YYYY
If the adverse event start date is completely missing, it will be set equal to treatment start date.
End Dates
Missing adverse event end dates will not be imputed. 
22.4
Data With Multiple Records
22.4.1
Dose Changes in Medication
Dose changes in medications are recorded on multiple rows in the dataset, with different start 
and stop dates. When classifying medications into categories (see section 9), each dose is 
considered a separate medication, and the same medication can be assigned to several 
categories for the same participant. Within a category, multiple entries contribute as a single 
count.
22.4.2
Changes in Intensity or Seriousness of Adverse Events
Changes in adverse event intensity or seriousness are recorded on multiple rows in the dataset. 
An adverse event that changes in intensity or seriousness in a period will contribute to the 
count of events as a single event.
In summaries of adverse events presented by intensity, the maximum intensity of the adverse 
event will be used. The maximum intensity is searched for in events with changes, as well as 
over repeated events based on the preferred term. Adverse events for which information on 
intensity is missing will be classified as severe.


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Adverse events for which information on seriousness is missing will be classified as serious.


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References
1.
Little R and Yau L. Intent-to-treat analysis for longitudinal studies with drop-outs. Biometrics. 
1996; 52: 1324-1333.
2.
Rubin, DB. Multiple imputation for nonresponse in surveys. New York: Wiley; 1997.
3. 
Ratitch B, Lipkovich I, O’Kelly M. Combining analysis results from multiply imputed categorical 
Data. PharmaSUG. 2013; Paper SP03.
4.
United States Food and Drug Administration (US FDA). Guidance for Industry: Drug-induced 
liver injury: premarketing clinical evaluation. July 2009.
 
 
 
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Statistical Analysis Plan
Authentication and Authorization


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Statistical Analysis Plan
Authentication and Authorization
Trial title:
Interventional, randomised, double-blind, parallel-group,
placebo-controlled trial of Lu AG09222 for the prevention of migraine in patients 
with unsuccessful prior preventive treatments
Trial No.:
19678A
SAP date:
29 March 2023
This document has been signed electronically. The signatories are listed below.
Authentication
Authorization
PPD
PPD
PPD
PPD
PPD
PPD


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Trial Procedures and Assessments


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Trial Procedures and Assessments
Table 1
Trial 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)


 
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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
Randomization

Efficacy Assessments
eDiary daily recordingf,g

j



c,k
 k
 k
 
 
Safety Assessments
Adverse events

 m,n,o






Blood and urine sampling for clinical safety 
laboratory tests

 m





Blood sampling for ADA including NAb
 m



p

Vital signs (including body temperature), weight, 
ECGs

 m,n





Examinations (physical)q

 m



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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
Examinations (neurological)q

 m

C-SSRSr

 m





 
m

 
m

 
m
 
m



Other Trial Procedures and Assessments
IMP administered (IV infusion)t
u
IMP accountabilityv

Concomitant medication (prescription and non-
prescription), herbal remedies, non-
pharmacological interventions, vitamin, and 
mineral supplements 
m






Substance use (alcohol, tobacco, caffeine, 
marijuana)
m



eDiary trainingf

eDiary closeoutk



Pregnancy testw

m




ADA = anti-drug antibodies; AE = adverse event; anti-HBc = hepatitis B core antibody; anti-HBs = hepatitis B 
surface antibody; anti-HCV = hepatitis C virus antibody; 
 
β-hCG = beta-human chorionic gonadotropin; 
 BL = baseline; 
 
 C-SSRS = Columbia-Suicide Severity Rating Scale; DNA = 
deoxyribonucleic acid; ECG = electrocardiogram; eCRF = electronic case report form; eDiary = electronic 
diary; EFU = efficacy follow-up; 
; FSH = follicle-stimulating 
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hormone; HBsAg = hepatitis B surface antigen; 
 
 IMP = investigational medicinal product; IV = intravenous; 
 
; MOH = medication overuse headache; 
 
; NAb = neutralizing antibodies; PACAP 
= pituitary adenylate cyclase-activating peptide; 
 PO = primary 
outcome; 
; RNA = ribonucleic acid; SCR = screening; SFU = safety follow-
up; WD = withdrawal
a.
All assessments may be completed over a maximum of 2 consecutive days with the exception of 
 
(see footnote i below); if so, the first day is considered the “visit” day according to the schedule. 
b.
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.
c.
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 scheduled 12 weeks after administration of the 
IMP (the Baseline Visit). At the Safety Follow-up Visit, patients will not be required to complete 
efficacy assessments. The eDiary assessments should continue on a daily basis until Week 4: 

If the Withdrawal Visit takes place during the treatment period and prior to Week 3, the patient will 
be contacted via phone for an Efficacy Follow-up (telephone contact) Visit at Week 4 for the 
eDiary closeout. 

If the patient withdraws between Week 3 and Week 4, then the Withdrawal Visit should be 
scheduled at Week 4 for the eDiary closeout and thus an Efficacy Follow-up (telephone contact) 
Visit at Week 4 is not required. 
d.
Patients must have adequately documented records of their previous migraine history. Patients with a 
concurrent diagnosis of MOH are allowed in the trial (at the Screening Visit, the investigator must 
confirm whether or not the patient has a concurrent diagnosis of MOH).
e.
The patients must have documented evidence of failure in the past 10 years of at least 2 to 4 (maximum) 
different pharmacological migraine preventive medications. Acceptable documentation of previous 
treatment failures includes (i) medical record with medication’s name, stop and start dates, dose level, 
and reasons for discontinuation or (ii) treating physician’s confirmation specific to each treatment. 
f.
At the Screening Visit, the patient must be assisted with the provisioning and training of the eDiary 
 
Details will be provided in a separate site information guide.
g.
The eDiary assessments will be completed in the remote setting on a daily basis.
h.
In addition to the eDiary compliance checks performed at the defined visits, ongoing evaluation of 
eDiary compliance will be performed by the site (based on eDiary reporting) and more frequent contact 
with patients may be needed in case of non-compliance.
i.
 
 
j.
Patients must complete the eDiary recording 
of headaches that ended prior to infusion (that is, for headaches which are ongoing or not yet recorded 
in the eDiary).
k.
The eDiary closeout will take place at the Safety Follow-up Visit while the patient is at the site. For 
patients who withdraw prior to the Primary Outcome Visit (Week 4), except for those who withdraw 
their consent, the eDiary closeout will take place at the Efficacy Follow-up (Phone Contact) Visit at 
Week 4 (or at the Withdrawal Visit if scheduled at Week 4). Details will be provided in separate 
training material.
l.
 
m. The following must be collected/completed prior to infusion: vital signs (including blood pressure, 
pulse, respiratory rate, and body temperature), concomitant medications, substance use, AEs, physical 
and neurological examinations, ECG, blood sampling (for clinical safety laboratory tests, 
, 
 ADA including NAb, 
), urine sampling (for 
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clinical safety laboratory and pregnancy tests), 
, and C-SSRS. Vital signs must be assessed 
prior to blood sampling.
n.
The following must be collected after infusion: vital signs (including blood pressure, pulse, respiratory 
rate, and body temperature), AEs and blood sampling 
. Vital signs must be 
assessed prior to blood sampling.
o.
Infusion-related reactions must be checked as part of the overall AE collection, during and after 
infusion, and before the patient is discharged from the site.
p.
A proportion of patients who complete the Safety Follow-up Visit (Week 12) will be asked to provide 
additional blood samples for post-trial immunogenicity testing at 12-week intervals (potentially up to 
12 months relative to the infusion date). The number of patients from whom these samples will be 
collected will be decided during the trial in consultation with the sponsor.
q.
For the Baseline Visit, examinations must be performed prior to the infusion. 
r.
The 
 C-SSRS will be administered by the authorized rater. For this trial, the following 
versions of the C-SSRS scale are used: the “Baseline/Screening” will be used at the Screening Visit and 
the “Since last visit” version will be used for all subsequent visits.
s.
 
t.
An unblinded pharmacist or designee is responsible for receiving, storing, and preparing the IMP. The 
pharmacist or designee will not be responsible for other aspects of the clinical trial where blinding is 
necessary.
u.
Patients must be monitored during the infusion and for a period of 2 hours from the EOI. Patients will 
be requested to stay longer should the investigator or designee determine this is clinically warranted.
v.
A designated unblinded clinical research associate is responsible for IMP accountability.
w.
For women of childbearing potential, a 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.
x.
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/trial 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 trial.
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.
 
 
 
 
 
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ICHD-3 Guidelines for Migraine


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ICHD-3 Guidelines for Migraine
1.1 Migraine without Aura
A. At least five attacks fulfilling criteria B–D
B. Headache attacks lasting 4–72 hours (when 
untreated or unsuccessfully treated)
C. Headache has at least two of the following four 
characteristics:
1.
unilateral location
2.
pulsating quality
3.
moderate or severe pain intensity
4.
aggravation by or causing avoidance of 
routine physical activity (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.


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Table 3
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference
Variable
CDISC Term
Unit
PCS Low
PCS High
Weight
WEIGHT
Kg
decrease ≥ 7%
increase ≥ 7%
Body Mass Index
BMI
kg/m2
decrease ≥ 7%
increase ≥ 7%
Pulse rate, 
supine/sitting/unknown
PULSE
beats/min
< 50 and
decrease ≥ 15
≥ 120 and
increase ≥ 15
Diastolic blood pressure,
supine/sitting/unknown
DIABP
mmHg
≤ 50 and
decrease ≥ 15
≥ 105 and
increase ≥ 15
Systolic blood pressure,
supine/sitting/unknown
SYSBP
mmHg
≤ 90 and
decrease ≥ 20
≥ 180 and
increase ≥ 20
Orthostatic systolic blood 
pressure
OBP
mmHg
≤ -30
Orthostatic pulse rate
OPR
beats/min
≥ 20
Temperature
TEMP
ºC
decrease ≥ 2
≥ 38.3 and
increase ≥ 2
Increase/decrease is relative to the baseline value.
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Table 4
PCS Criteria for ECG Parameters
ECG Parameter
CDISC Term
Unit
PCS Low
PCS High
Absolute Time Interval
PR interval
PRAG
Msec
≥ 260
QRS interval
QRSAG
Msec
≥ 150
QT interval
QTAG
Msec
≥ 500
Derived Time Interval
Heart rate
EGHRMN
beats/min
< 50 and
decrease ≥ 15
≥ 120 and
increase ≥ 15
QTcB interval
QTCBAG
Msec
< 300
> 500 or
increase > 60
QTcF interval
QTCFAG
Msec
< 300
> 500 or
increase > 60
Increase/decrease is relative to the baseline value.


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