Interventional, Open-label, Fixed-dose Multiple Administration Study to Evaluate Long-term Treatment With Eptinezumab in Patients With Chronic Cluster Headache
Phase: PHASE3
Conditions: Chronic Cluster Headache
Sponsor: H. Lundbeck A/S

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Study 19385A – Clinical Study Protocol
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Clinical Study Protocol
Interventional, open-label, fixed-dose multiple administration 
study to evaluate long-term treatment with eptinezumab in 
patients with chronic cluster headache
Eptinezumab
Study No.:
19385A (CHRONICLE)
EudraCT/IND No.:
2020-001968-28 / 151358
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
2.0
Date of edition:
25 November 2021
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NCT05064397

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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 authorisation 
from H. Lundbeck A/S.
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Synopsis – Study 19385A
Sponsor
H. Lundbeck A/S
Investigational Medicinal Product
Eptinezumab
Study Title
Interventional, open-label, fixed-dose multiple administration study to evaluate long-term treatment with 
eptinezumab in patients with chronic cluster headache 
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To evaluate the long-term safety and 
tolerability of eptinezumab in patients with 
chronic cluster headache (cCH)
Endpoints for the primary objective:
adverse events
absolute values and changes from baseline in clinical 
safety laboratory test values, vital signs, weight, and 
electrocardiogram (ECG) parameter values
potentially clinically significant (PCS) clinical safety 
laboratory test values, vital signs, weight changes, and 
ECG parameter values
development of specific anti-eptinezumab antibodies 
(ADA) including neutralizing antibodies (NAbs)
Columbia-Suicide Severity Rating Scale (C-SSRS) score
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Secondary Objectives
To evaluate the efficacy of eptinezumab in 
patients with cCH
Endpoints for the secondary objective (efficacy):
Conversion from cCH to episodic cluster headache
(Week 0 to Week 48): Number of patients with no cluster 
headache attacks for ≥3 consecutive months 
(≥13 consecutive weeks)
Change from baseline in weekly number of times an 
abortive therapy (oxygen and/or triptans) was used 
(calculated for each infusion with eptinezumab, taking the 
average across the first 4 weeks after the infusion)
Change from baseline in the average number of weekly
attacks (calculated for each infusion with eptinezumab,
taking the average across the first 4 weeks after the
infusion)
Change from baseline in the 5-point self-rating pain
severity scale (calculated for each infusion with
eptinezumab, taking the average across the first 4 weeks 
after the infusion)
Response: ≥30% reduction in number of weekly attacks
(calculated for each infusion with eptinezumab, based on
the average across the first 4 weeks after the infusion)
Response: ≥50% reduction in number of weekly attacks
(calculated for each infusion with eptinezumab, based on
the average across the first 4 weeks after the infusion)
cCH remission (Week 0 to Week 48): Number of patients
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks)
cCH remission (Week 0 to Week 12): Number of patients
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks between the first and second 
infusion)
cCH remission (Week 12 to Week 24): Number of patients 
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks between the second and third 
infusion)
cCH remission (Week 24 to Week 36): Number of patients 
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks between the third and fourth 
infusion)
cCH remission (Week 36 to Week 48): Number of patients 
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks within the first 12 weeks after the 
fourth infusion)
Number of patients who received a transitional therapy
during the Treatment Period (Week 0 to Week 48)
Patient Global Impression of Change (PGIC) score
(assessed monthly after the first eptinezumab infusion)
Change from baseline in Sleep Impact Scale (SIS) domain
scores (at each infusion and 4 weeks after each infusion)
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Secondary Objectives (continued)
To evaluate the efficacy of eptinezumab in 
patients with cCH (continued)
Exploratory endpoints for the secondary objective 
(efficacy):
Change from baseline in the average number of monthly 
attacks (per 4-week intervals after each eptinezumab 
infusion)
Change from baseline in the 5-point self-rating pain 
severity scale (taking the average across 4-week intervals 
after each eptinezumab infusion)
Response: ≥30% reduction in number of monthly attacks
by 4-week intervals after each eptinezumab infusion, and
for each of the periods between infusions with
eptinezumab, and for 12 weeks after the last eptinezumab
infusion
Response: ≥50% reduction in number of monthly attacks
by 4-week intervals after each eptinezumab infusion, and
for each of the periods between infusions with
eptinezumab, and for 12 weeks after the last eptinezumab
infusion
Response: 100% reduction in number of monthly attacks
by 4-week intervals after each eptinezumab infusion, and
for each of the periods between infusions with
eptinezumab, and for 12 weeks after the last eptinezumab
infusion
Change from baseline in monthly number of times an
abortive therapy (oxygen and/or triptans) was used 
(per 4-week interval after each eptinezumab infusion)
To evaluate the efficacy of eptinezumab on 
health-related quality of life, health care 
resource utilization, and work productivity
Endpoints for the secondary objective:
Change from baseline in EuroQol 5-Dimension 5-Level
(EQ-5D-5L) at Weeks 4, 16, 28, 40 and 48
Health Care Resources Utilization (HCRU) at baseline, 
Weeks 4, 16, 28, 40 and 48
Change from baseline in the Work Productivity Activity 
Impairment: General Health second version 
(WPAI:GH2.0) sub-scores (Absenteeism, Presenteeism, 
Work productivity loss, Activity impairment) at Weeks 4, 
16, 28, 40 and 48
Exploratory Objective
To explore the target engagement of 
eptinezumab to calcitonin gene-related 
peptide (CGRP) 
Endpoint for the exploratory objective:
Change from baseline to each study time point in CGRP: 
CGRP-eptinezumab complex, free CGRP
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Study Methodology
This is an interventional, open-label, fixed-dose multiple administration study to evaluate the long-term 
treatment with eptinezumab in patients with cCH.
The target population for this study is defined as patients with cCH, based on the International Headache 
Society International Classification of Headache Disorders third edition (IHS ICHD-3) classification, with 
documented evidence of cCH prior to screening and confirmed via prospectively-collected information in the 
eDiary during the Screening Period.
The total study duration from the Screening Visit to the Safety Follow-up (SFU) Visit is approximately 
60 weeks and includes Screening Period (4 weeks), Treatment Period (48 weeks), and SFU Period (8 weeks).
Eligible patients will receive four infusions with eptinezumab 400 mg at 12-week intervals at Day 0 (Visit 2), 
at the end of Weeks 12 (Visit 5), 24 (Visit 8) and 36 (Visit 11), administered as an intravenous (IV) infusion 
over 45 minutes (+15 minutes).
The SFU Visit will take place at Week 56 (Visit 15) that is 20 weeks (5 half-lives) after the last eptinezumab 
administration.
Patients who withdraw from the study, except for those who withdraw their consent, will be asked to attend a 
Withdrawal Visit as soon as possible and a further SFU Visit, scheduled 20 weeks (5 half-lives) after the last 
eptinezumab administration.
Patients who are withdrawn from the treatment will be given the opportunity to remain in the study at the 
discretion of the investigator. Patients will be expected to attend all scheduled study visits and procedures 
except eptinezumab administration. If patients refuse, they will be asked to attend a Withdrawal Visit as soon 
as possible and a further SFU Visit, scheduled 20 weeks (5 half-lives) after the last eptinezumab 
administration.
Eligibility will be assessed during the Screening Period and before the first administration of eptinezumab at 
the Baseline Visit (Day 0/Visit 2).
Study visits:
The following visits will be site visits: Screening Visit at Week -4 (Visit 1), Investigational Medicinal 
Product (IMP) Visits at Weeks 0, 12, 24 and 36 (Visits 2, 5, 8 and 11), Completion Visit at Week 48 
(Visit 14) and SFU Visit at Week 56 (Visit 15) or Withdrawal Visit, if applicable.
All other study visits will be phone contact visits.
In exceptional situations to be approved by the Contract Research Organisation’s (CRO) medical monitor, 
site visits may only consist of blood and urine sampling (for clinical safety laboratory tests, exploratory
eptinezumab quantification, ADA including NAb, and exploratory biomarkers), ECG, vital signs, physical 
and neurological examinations, adverse events recording, and eptinezumab administration, while the 
remaining assessments (eDiary, electronic patient-reported outcomes [ePROs], C-SSRS, and investigator 
evaluations) can be conducted remotely as virtual clinic visits in line with the United States Food and Drug 
Administration (US FDA) and European Medicines Agency (EMA) guidance.
Patients will be assigned an eDiary at the beginning of the Screening Period (Visit 1, Week -4) and will be 
required to complete it:
Daily - during the Screening Period (from Week -4 to Day 0) and during the first 4 weeks that follow each 
eptinezumab infusion (Weeks 1 to 4, 13 to 16, 25 to 28, and 37 to 40).
Weekly - for Weeks 5 to 12, 17 to 24, 29 to 36, and 41 to 48.
During the study visits with eptinezumab infusion, eDiary and ePROs must be completed prior to infusion and 
prior to any interaction with the clinical site staff.
At these visits, safety assessments will be performed before and after the infusion. Safety assessments before 
eptinezumab infusion consists of vital signs including body temperature, weight, concomitant medications, 
adverse events, ECG, blood sampling (for clinical safety laboratory tests, exploratory eptinezumab
quantification, and ADA including NAb), urine sampling (for clinical safety laboratory and pregnancy tests) 
and C-SSRS. Safety assessments after eptinezumab infusion consists of vital signs including body 
temperature, and adverse events.
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Blood samples for exploratory eptinezumab quantification, and ADA and NAbs assessments will be collected 
at Visits 2, 5, 8, 11, 14 (or at Withdrawal Visit for patients, who withdraw from the study) and at SFU Visit 
(Visit 15).
The study design is presented in Panel 1 (including the study periods) and the scheduled study procedures and 
assessments are summarised in Panel 2.
Number of Patients Planned
125 patients recruited from specialist settings are planned to be enrolled and receive treatment with 
eptinezumab, allowing for 100 patients to complete.
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Target Patient Population
Main Inclusion Criteria
The patient has a diagnosis of cCH as defined by IHS ICHD-3 classification with a history of cCH of at 
least 12 months prior to the Screening Visit.
The patient has a medical history of onset of cluster headache at ≤50 years of age.
The patient has an adequately documented record of previous abortive, transitional and preventive 
medication use for cCH, for at least 12 months prior to the Screening Visit.
The patient has during the Screening Period, based on prospectively-collected information in the eDiary, a 
cluster headache attack frequency of (this requirement should not be shared with the patient):
a.
minimum of 14 cluster headache attacks for the 28-day Screening Period
The patient is able to distinguish cluster headache attacks from other headaches (such as tension-type 
headaches, migraine).
The patient has demonstrated compliance with the eDiary by entry of data for at least 24 out of 28 days 
during the 4-week Screening Period.
The patient is aged ≥18 and ≤75 years at the Screening Visit.
Main Exclusion Criteria
The patient has experienced failure on a previous treatment targeting the CGRP pathway (anti-CGRP 
monoclonal antibodies [mAbs] and gepants).
The patient has a history of severe drug allergy or hypersensitivity or known hypersensitivity or intolerance 
to the IMP or its excipients.
The patient has confounding and clinically significant pain syndromes (for example, fibromyalgia, complex 
regional pain syndrome).
The patient has a history or diagnosis of chronic paroxysmal hemicrania.
The patient has a history or diagnosis of chronic tension-type headache, hypnic headache, hemicrania 
continua, new daily persistent headache, chronic migraine or unusual migraine subtypes such as hemiplegic 
migraine (sporadic and familial), recurrent painful ophthalmoplegic neuropathy, migraine with neurological 
accompaniments that are not typical of migraine aura (diplopia, altered consciousness, or longer than 
1 hour).
Patients with a history of epilepsy.
Patients with 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 the Screening Visit.
The patient is, at the Screening Visit or at the Baseline Visit, at significant risk of suicide (either in the 
opinion of the investigator or defined, using the C-SSRS, as the patient answering: "yes" to suicidal ideation 
questions 4 or 5 or answering: "yes" to suicidal behaviour within the past month). Patients who do not meet 
this criterion, but who are considered by the investigator to be at significant risk for suicide, are excluded.
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).
The patient has been previously tested positive for human immunodeficiency virus (HIV), hepatitis B 
surface antigen (HBsAg) or Hepatitis C virus antibody (anti-HCV).
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The following recent and concomitant medications are disallowed or allowed with restrictions prior to or 
during the study (the list is not comprehensive):
a.
Anti-CGRP therapies are disallowed for ≤5 half-lives for mAbs and ≤1 month for gepants 
prior to the Screening Visit.
b.
Botulinum toxin type A or B, administered in the head or neck area for treatment of cluster 
headache or other disorders, or for cosmetic use, is disallowed for 4 months prior to the 
Screening Visit and until the SFU Visit.
c.
Psilocybin (mushrooms), lysergic acid diethylamide (LSD), or 2-bromo-LSD, or other illegal 
drugs are disallowed for two months prior to the Screening Visit and until the SFU Visit.
d.
Greater occipital nerve (GON) block, injected and oral steroids (used for headache treatment) 
are disallowed for 30 days prior to the Screening Visit and during the Screening Period.
e.
Injected and oral steroids for indications other than CH:
i.
Disallowed during the Screening Period 
ii.
Short-term treatment (maximum 3 days, followed by potential tapering) is allowed 
from Baseline until the SFU Visit   
f.
The following therapies are disallowed for 30 days prior to the Screening Visit and until the 
SFU Visit:
i.
any other cranial or extracranial nerve block;
ii.
any neuromodulation treatment;
iii.
gamma knife or other invasive procedures.
g.
Methergine is disallowed for 14 days prior to the Screening Visit and until the SFU Visit.
h.
The following recent and concomitant medications are allowed with restrictions prior to or 
during the study (the list is not comprehensive): Stable dose (with restrictions on the maxi-
mum dose for lithium only) for 1 month prior to the Screening Visit and during the Screening 
Period: verapamil, topiramate, gabapentin, valproate, candesartan, lithium and indomethacin. 
Initiation, discontinuation and change of dose are allowed during the Treatment Period and 
the SFU Period, if clinically indicated.
i.
Melatonin is allowed at any time. Initiation, discontinuation and dose modification are al-
lowed during the Treatment Period and the SFU Period.
j.
Dihydroergotamine is disallowed for use as a preventive treatment.
k.
Abortive therapies for cluster headache attack are allowed at any time during the study: high-
flow oxygen; oral triptans, sumatriptan subcutaneous injection; sumatriptan nasal spray; 
zolmitriptan nasal spray; acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), 
dihydroergotamine (allowed for not more than 3 times per week) or ergot derivatives, oc-
treotide.
l.
Opioids and cannabinoids are allowed with restrictions.
Investigational Medicinal Product, Dose and Mode of Administration
Eptinezumab – 400 mg, concentrate for solution for infusion 100 mg/mL added to 100 mL of 0.9% normal 
saline, intravenously.
Eptinezumab will be administered at Day 0 and at Weeks 12, 24 and 36, by IV infusion over 45 minutes 
(+15 minutes).
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Assessment Details
The assessments are summarised in Panel 2. Details for selected assessments which are non-standard/require 
more explanation/description are provided below. All scales used to assess efficacy and pharmacoeconomic 
information in this study, are patient-reported instruments.
eDiary
Patients will complete a cluster headache eDiary daily during the Screening Period (from Week -4 to Day 0) 
and during the first 4 weeks that follow each eptinezumab infusion (Weeks 1 to 4, 13 to 16, 25 to 28, and 37 to 
40) and weekly for Weeks 5 to 12, 17 to 24, 29 to 36, and 41 to 48. The eDiary consists of applications and 
reports which will be used to derive the cluster headache endpoints and abortive medication use. The eDiary 
will be distributed to each patient at the Screening Visit after patient training on eDiary use by the clinical site 
staff. The eDiary data from the 4-week Screening Period will be used to determine eligibility criteria, baseline 
cluster headache characteristics and eDiary compliance. Ongoing evaluation of eDiary compliance will be 
performed by the clinical site based on eDiary reports.
Sleep Impact Scale (SIS)
The SIS is a patient-reported scale to assess quality of life resulting from sleep disturbance. The SIS domains 
cover sleep impact on daily activities, emotional well-being, emotional impact, energy/fatigue, social well-
being, mental fatigue, and satisfaction with sleep. Each item is rated on a scale ranging from 1 (always/all of the 
time/very satisfied) to 5 (never/none of the time/very dissatisfied). Scores by domains are ranging from 0 to 
100; items within each domain are summed and transformed using a formula. A higher score indicates better 
quality of life.
Health Care Resource Utilization (HCRU)
Cluster headache-specific HCRU information will be collected in terms of outpatient health care professional 
visits, emergency room visits, hospital admissions, as well as duration of hospital stays during the past 4 weeks. 
Clinical site personnel and patients will be instructed to capture utilization that takes place outside of visits 
associated with their participation in the clinical study.
Statistical Methodology
The following analysis sets will be used to analyse and present the data:
all-patients-enrolled set (APES) - all-patients-enrolled
all-patients-treated set (APTS) - all patients in the APES who receive infusion with eptinezumab
full-analysis set (FAS) - all patients in the APTS who have a valid assessment of the baseline number of 
monthly attacks and a post-baseline assessment of number of monthly attacks.
The safety and tolerability analyses, and the exposure, disposition, and demographics and baseline 
characteristics will be based on the APTS. The efficacy analyses will be based on the FAS.
Primary analysis
The primary objective of the study is to evaluate the long-term safety and tolerability of eptinezumab in 
patients with cCH. This will be evaluated based on the collected data on adverse events, vital signs, weight, 
ECGs, clinical safety laboratory test values, C-SSRS, ADA and NAbs. Adverse events will be summarised for 
the full study and by 3-month periods, absolute values and changes from baseline for vital signs, weight, 
ECGs, clinical safety laboratory test values will be summarised by visit. The number of patients exceeding the 
PCS values will be tabulated. The incidence, kinetics and magnitude of ADA and NAb response(s) will be 
evaluated.
Secondary analysis
Details on derivations and imputations of eDiary data (daily or weekly data entries), as well as sub-group 
analyses, will be described in the Statistical Analysis Plan (SAP).
For continuous endpoints, descriptive statistics for absolute values and changes from baseline, when 
appropriate, will be provided by visit. In addition, continuous endpoints will be modelled using mixed models 
for repeated measurements (MMRM) including baseline score, visit and baseline interacting with visit, if 
applicable. The estimated means, standard errors and confidence intervals (CIs) will be provided by visit. For 
response variables the counts, percentages and CI will be presented by visit. 
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Testing Strategy
No formal testing will be done. 
Sample Size Considerations
In line with the International Council for Harmonisation (ICH) E1 guideline,1 this study aims at providing data 
in 100 patients exposed to eptinezumab for 1 year. Dodick (2020),2 in patients suffering from cCH included in a 
12-week study, reports less than 4% withdrawals. In the European Union Drug Regulating Authorities Clinical 
Trials (EudraCT) report for study NCT02964338,3 in patients suffering from cCH, approximately 7% of 
patients dropped out from the first 12-week period; the withdrawals due to the “sponsor terminated study” are 
not included as a reason for withdrawal. As the withdrawal rate for a long-term study like the current study is 
unknown, 125 patients are planned to be enrolled and treated, allowing for 100 patients to complete, with a 
withdrawal rate of 20%. The withdrawal rate will be monitored during the study conduct, and if a clear 
deviation from the assumed withdrawal rate is observed, the number of patients enrolled and treated might be 
increased to ensure that data is available for a sufficient number of patients with long-term exposure. 
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Panel 1
Study Design
The study consists of Screening Period (4 weeks), Treatment Period (48 weeks), and SFU Period (8 weeks). 
Eligible patients will receive four IV infusions with eptinezumab 400 mg administered at 12-week intervals. For 
all patients who complete the study, a SFU Visit will be conducted 20 weeks (5 half-lives) after the last infusion 
of eptinezumab, that is at Week 56 (Visit 15). For patients who withdraw from the study, the SFU Visit will be 
conducted 20 weeks (5 half-lives) after their last eptinezumab infusion.
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Panel 2
Study Procedures and Assessments
Visit Name
Screening Period
IMP
Phone contact
Phone contact
IMP
Phone contact
Phone contact
IMP
Phone contact
Phone contact
IMP
Phone contact
Phone contact
Completion 
Safety Follow-up c
Withdrawal d
Visit Number
1a, z
2a
3b
4b
5a
6b
7b
8a
9b
10b 11a 12b 13b 14a 15a
WDa
End of Week
-4
0
4
8
12
16
20
24
28
32
36
40
44
48
56
Visit Window e (days 
relative to nominal 
visit)
+3
3
3
3
3
3
3
3
3
3
3
3
3
+3
Screening and Baseline Procedures and Assessments
Signed informed con-
sent(s) f, z

Demographics (age, sex, 
race)

Diagnosis

Disease-specific history g

Relevant history (social, 
medical, psychiatric, neu-
rological)

Previous cluster headache 
abortive, transitional and 
preventive therapy use g

Recent medication (past 
3 months)

Substance use (for exam-
ple smoking and alcohol)

Height

Family history of cluster 
headache

Urine drug screen

Inclusion/exclusion crite-
ria


Efficacy Assessments (ePROs) h, i
eDiary recording j, k














eDiary compliance check 
l














PGIC k













SIS k










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Visit Name
Screening Period
IMP
Phone contact
Phone contact
IMP
Phone contact
Phone contact
IMP
Phone contact
Phone contact
IMP
Phone contact
Phone contact
Completion 
Safety Follow-up c
Withdrawal d
Visit Number
1a, z
2a
3b
4b
5a
6b
7b
8a
9b
10b 11a 12b 13b 14a 15a
WDa
End of Week
-4
0
4
8
12
16
20
24
28
32
36
40
44
48
56
Visit Window e (days 
relative to nominal 
visit)
+3
3
3
3
3
3
3
3
3
3
3
3
3
+3
Pharmacoeconomic Assessments (ePROs) h, i
EQ-5D-5L k







HCRU k







WPAI:GH2.0 k







Pharmacokinetic Assessments
Blood sampling for ex-
ploratory eptinezumab
quantification m, s







Pharmacodynamic Assessments (exploratory biomarkers)
Blood sampling for phar-
macodynamic/explora-
tory biomarkers m, s






Safety Assessments
Adverse events n, o, y
















Blood and urine sampling 
for clinical safety labora-
tory tests n








Blood sampling for ADA 
including NAbs n, u







Vital signs n, o (including 
body temperature), 
weight








ECG n








Examinations (physical, 
neurological) p








C-SSRS n, q








Biobanking r
Blood sampling for gene 
expression profiling 
(RNA) s



Blood sampling for 
metabolomics/proteomics
(plasma) s



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Visit Name
Screening Period
IMP
Phone contact
Phone contact
IMP
Phone contact
Phone contact
IMP
Phone contact
Phone contact
IMP
Phone contact
Phone contact
Completion 
Safety Follow-up c
Withdrawal d
Visit Number
1a, z
2a
3b
4b
5a
6b
7b
8a
9b
10b 11a 12b 13b 14a 15a
WDa
End of Week
-4
0
4
8
12
16
20
24
28
32
36
40
44
48
56
Visit Window e (days 
relative to nominal 
visit)
+3
3
3
3
3
3
3
3
3
3
3
3
3
+3
Blood sampling for phar-
macogenetics (DNA) 
(optional) t

Blood sampling for pos-
sible future ADA assess-
ment u






Other Study Procedures and Assessments
IMP administered (IV in-
fusion) v




IMP accountability




Concomitant medication 
(prescription and non-
prescription) n
















eDiary training i

ePRO training i

eDiary closeout w


Pregnancy test n, x







ADA = anti-drug antibody; C-SSRS = Columbia-Suicide Severity Rating Scale; DNA = deoxyribonucleic acid; 
ECG = electrocardiogram; EQ-5D-5L = EuroQol 5-Dimension 5-Level; HCRU = Health Care Resources Utili-
zation; IMP = investigational medicinal product; IV = intravenous; NAbs = neutralizing antibodies; PGIC = Pa-
tient Global Impression of Change; ePRO = electronic patient-reported outcome; RNA = ribonucleic acid; SIS = 
Sleep Impact Scale; WD = Withdrawal; WPAI:GH2.0 = Work Productivity Activity Impairment: General Health
second version.
a
This visit should be a site visit.
b
For phone visits, the patient will be contacted for eDiary compliance check, to ensure that the selected assess-
ments have been completed and for collection of relevant information such as adverse events and concomi-
tant medications.
c
The SFU Visit should be scheduled 20 weeks (5 half-lives) after the last eptinezumab administration.
d
Patients who withdraw from the study, except for those who withdraw their consent, will be asked to attend a 
Withdrawal Visit as soon as possible.
e
If the date of a clinic visit or phone contact does not conform to the schedule, subsequent visits should be 
planned to maintain the visit schedule relative to the Baseline Visit (Day 0/Visit 2).
f
At the Screening Visit, the patient will be asked to sign the main Informed Consent Form (ICF), and the ICF
for blood sampling for pharmacogenetics (optional). Depending of the country requirements, the number of 
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ICFs may be different. Under exceptional circumstances, the discussion with the patients about the Informed 
Consent Form(s) can be done as a virtual clinic visit and the Informed Consent Form(s) can be provided re-
motely in line with the US FDA and EMA guidances. According to the EMA guidance, this could comprise 
contacting the patients via phone or video-calls and obtaining oral consents, to be documented in the patients' 
medical records, supplemented with email confirmation. Any consent obtained this way should be docu-
mented and confirmed by way of normal consent procedures at the earliest opportunity when the patients are 
back at the clinical sites.
g
Patients must have adequately documented records or reliable history of cCH and previous treatment for cCH
within the 12 months prior to the Screening Visit. See protocol (section 12) for definition of adequately docu-
mented records.
h
During the Treatment Period, ePROs which are scheduled in alignment with a clinic visit can be completed in 
the clinic or in the remote setting within 3 days prior to the scheduled clinic visit date. ePROs which are 
scheduled in alignment with a phone contact must be completed in the remote setting and can be completed 
on the day or within 3 days prior to the scheduled phone contact date.
i
At the Screening Visit, the patient must be assisted with the provisioning and training of the eDiary and 
ePROs. Details will be provided in a separate training module.
j
Patients must complete the eDiary daily during the Screening Period (from Week -4 to Day 0) and during the 
first 4 weeks that follow each eptinezumab infusion (Weeks 1 to 4, 13 to 16, 25 to 28, and 37 to 40) and 
weekly for Weeks 5 to 12, 17 to 24, 29 to 36, and 41 to 48.
k
Patients must complete the daily eDiary and ePRO entries prior to infusion and prior to any interaction with 
the clinical site staff.
l
In addition to the eDiary compliance checks performed at the defined study visits, ongoing evaluation of eDi-
ary compliance will be performed by the clinical site (based on eDiary reporting) and more frequent contact 
with patients may be performed in case of non-compliance.
m At IMP Visits, two blood samples will be collected for exploratory eptinezumab quantification and explora-
tory biomarkers – one sample prior to the eptinezumab infusion and one sample 1 hour after the end of the 
infusion.
n
Infusion must be preceded by the assessment of vital signs (including body temperature), weight, concomi-
tant medications, adverse events, ECG, blood sampling (for clinical safety laboratory tests, exploratory epti-
nezumab quantification, ADA including NAb, and exploratory biomarkers), urine sampling (for clinical 
safety laboratory and pregnancy tests) and C-SSRS. Vital signs must be assessed prior to blood sampling.
o
Vital signs (including body temperature) and adverse events must be checked both prior to and after infusion. 
Vital signs must be assessed prior to blood sampling.
p
Physical and neurological examinations for all clinic visits after the Screening Visit are to be conducted at the 
discretion of the investigator. If these examinations are conducted at an IMP Visit, these must be performed 
prior to the infusion.
q
C-SSRS will be administered by the authorised rater at the clinic.
r
Biobank may be excluded or optional per local regulation.
s
Exploratory gene expression profiling (ribonucleic acid [RNA]) and metabolomics/proteomics, including 
blood sampling for exploratory eptinezumab quantification, ADA biobanking and exploratory biomarkers, is 
covered by the main Informed Consent Form.
t
Sampling for pharmacogenetics is optional and covered by a separate Informed Consent Form.
u
Blood samples for safety ADA/NAb assessments and ADA biobanking (possible future analysis) will be
drawn at Day 0/Visit 2, prior to the second eptinezumab infusion (Week 12/Visit 5), prior to the third epti-
nezumab infusion (Week 24/Visit 8), prior to the fourth eptinezumab infusion (Week 36/Visit 11), Comple-
tion Visit (Week 48/Visit 14), SFU Visit (Week 56/Visit 15). A Withdrawal Visit (if the patient withdraws) 
sample will only be drawn for the safety ADA/NAb assessments when applicable.
v
Patients must be monitored during the infusion and for a period of 1 hour from the end of infusion. Patients
will be requested to stay longer should the investigator or designee determine this is clinically warranted.
w The eDiary closeout will take place at Completion Visit (Week 48/Visit 14) / Withdrawal Visit (for patients 
who withdraw). Details will be provided in a separate training module.
x
For women of childbearing potential, pregnancy test at the Screening Visit and the SFU Visit is to be 
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conducted using serum beta-human chorionic gonadotropin (β-hCG). At all other visits, urine pregnancy test-
ing will be performed and in case of a positive finding, further confirmatory testing will be performed via 
serum β-hCG.
y
Adverse events (serious and non-serious) must be collected, recorded, and reported to Lundbeck from the
time the patient has signed the Informed Consent Form(s) at the Screening Visit. Pre-treatment adverse 
events will also be collected.
z
The Screening Visit assessments may be extended over several days if needed. The date of the first assess-
ment (except Informed Consent Form) should be entered in the electronic case report form (eCRF) as the 
visit date. eDiary must be provided to the patient on the date of that first assessment, which is considered as 
the first day of the 28-day Screening Period.
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Table of Contents
List of Panels........................................................................................................................... 23
List of Abbreviations and Definitions of Terms..................................................................... 24
Major Changes Since Last Edition......................................................................................... 26
1
Introduction.................................................................................................................... 27
1.1
Background........................................................................................................... 27
1.1.1
Overview ............................................................................................... 27
1.1.2
Nonclinical Data .................................................................................... 28
1.1.3
Clinical Data.......................................................................................... 29
1.2
Rationale for the Study.......................................................................................... 30
2
Objectives and Endpoints............................................................................................... 31
3
Study Design................................................................................................................... 33
3.1
Overview of the Study Design............................................................................... 33
3.2
Rationale for the Study Design.............................................................................. 35
3.3
Benefit-Risk Assessment....................................................................................... 37
4
Ethics .............................................................................................................................. 39
4.1
Ethical Rationale................................................................................................... 39
4.2
Informed Consent.................................................................................................. 41
4.3
Personal Data Protection ....................................................................................... 43
4.4
Ethics Committees and Institutional Review Boards.............................................. 44
5
Study Population ............................................................................................................ 44
5.1
Number of Patients and Regions............................................................................ 44
5.2
Patient Recruitment............................................................................................... 44
5.3
Selection Criteria .................................................................................................. 44
6
Investigational Medicinal Product................................................................................. 48
6.1
Treatment Regimen............................................................................................... 48
6.2
Withdrawal Criteria............................................................................................... 48
6.3
IMP, Formulation, and Strength ............................................................................ 49
6.4
Manufacturing, Packaging, Labelling, and Storage of IMP .................................... 49
6.5
Method of Assigning Patients to Treatment ........................................................... 50
6.6
IMP Accountability............................................................................................... 50
7
Concomitant Medication................................................................................................ 50
8
Study Visit Plan.............................................................................................................. 51
8.1
Overview .............................................................................................................. 51
8.2
Screening Visit (Visit 1)........................................................................................ 53
8.2.1
Pre-Screening......................................................................................... 53
8.2.2
Patient Identification Card...................................................................... 53
8.2.3
Re-Screening Visit ................................................................................. 54
8.2.4
Extension of Screening Period................................................................ 55
8.3
Baseline Visit (Day 0/Visit 2) + IMP infusion ....................................................... 56
8.4
IMP Visits (Visits 2, 5, 8 and 11) + IMP infusion.................................................. 56
8.5
Phone Contacts (Visits 3, 4, 6, 7, 9, 10, 12, 13)...................................................... 57
8.6
Completion Visit (Visit 14)................................................................................... 58
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8.7
Withdrawal Visit................................................................................................... 58
8.8
Safety Follow-up Visit (Visit 15)........................................................................... 59
8.9
Unscheduled Visit................................................................................................. 59
8.10
End-of-study Definition ........................................................................................ 59
9
Assessments .................................................................................................................... 60
9.1
Screening and Baseline Procedures and Assessments............................................. 60
9.1.1
Demographics and Baseline Characteristics............................................ 60
9.1.2
Diagnostic Assessments ......................................................................... 61
9.1.3
Drug Screen ........................................................................................... 62
9.2
Efficacy Assessments............................................................................................ 62
9.2.1
Clinical Outcome Assessments............................................................... 62
9.2.1.1
Use of Clinical Outcome Assessments Tools........................... 62
9.2.1.2
eDiary .................................................................................... 63
9.2.1.3
Patient Global Impression of Change...................................... 64
9.2.1.4
Sleep Impact Scale ................................................................. 64
9.2.1.5
External Clinical Outcome Assessments Monitoring Oversight64
9.2.1.6
Clinical Outcome Assessments Tool Training......................... 65
9.3
Pharmacoeconomic Assessments........................................................................... 65
9.3.1
Clinical Outcome Assessments............................................................... 65
9.3.1.1
Use of Clinical Outcome Assessments Tools........................... 65
9.3.1.2
EuroQol 5 Dimension – 5 Levels............................................ 66
9.3.1.3
Health Care Resource Utilization............................................ 66
9.3.1.4
Work Productivity and Activity Impairment: General Health 
Second Version ...................................................................... 66
9.3.1.5
External Clinical Outcome Assessments Monitoring Oversight66
9.3.1.6
Clinical Outcome Assessments Training................................. 67
9.4
Pharmacokinetic Assessments (Blood Sampling for Exploratory Eptinezumab 
Quantification)...................................................................................................... 67
9.5
Pharmacodynamic Assessments (Exploratory Biomarkers).................................... 67
9.6
Safety Assessments............................................................................................... 68
9.6.1
Adverse Events ...................................................................................... 68
9.6.2
Clinical Safety Laboratory Tests............................................................. 68
9.6.3
Vital Signs ............................................................................................. 70
9.6.4
Height and Weight ................................................................................. 70
9.6.5
Electrocardiograms................................................................................. 70
9.6.6
Physical and Neurological Examinations................................................ 71
9.6.7
Columbia-Suicide Severity Rating Scale................................................. 71
9.6.8
Anti-Drug Antibody including Neutralizing Antibody Assessments........ 72
9.7
Biobanking ........................................................................................................... 72
9.7.1
General Considerations........................................................................... 72
9.7.2
Blood Sampling for Gene Expression Profiling....................................... 73
9.7.3
Blood Sampling for Metabolomics and/or Proteomics ............................ 73
9.7.4
Blood Sampling for Pharmacogenetics ................................................... 73
9.7.5
Blood Sampling for Possible Future Anti-Drug Antibody Assessments... 73
9.8
Order of Assessments............................................................................................ 74
9.9
Total Volume of Blood Drawn and Destruction of Biological Material.................. 74
9.10
Treatment Compliance .......................................................................................... 75
10
Adverse Events ............................................................................................................... 75
10.1
Definitions............................................................................................................ 75
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10.1.1
Adverse Event Definitions...................................................................... 75
10.1.2
Adverse Event Assessment Definitions................................................... 76
10.1.3
Management of Reactions to Study Drug................................................ 77
10.2
Pregnancy ............................................................................................................. 78
10.3
Recording Adverse Events .................................................................................... 78
10.4
Reporting Serious Adverse Events......................................................................... 79
10.5
Treatment and Follow-up of Adverse Events......................................................... 80
11
Data Handling and Record Keeping.............................................................................. 80
11.1
Data Collection ..................................................................................................... 80
11.1.1
Electronic Case Report Forms ................................................................ 80
11.1.2
Patient Binders....................................................................................... 81
11.1.2.1
Use of Patient Binders ............................................................ 81
11.1.2.2
Serious Adverse Event Fallback Forms................................... 81
11.1.3
External Data ......................................................................................... 81
11.2
Retention of Study Documents at the Clinical Site................................................. 81
11.2.1
eCRF Data ............................................................................................. 81
11.2.2
Other Study Documents.......................................................................... 82
12
Monitoring Procedures................................................................................................... 82
13
Audits and Inspections ................................................................................................... 83
14
Protocol Compliance ...................................................................................................... 83
15
Study Termination.......................................................................................................... 84
16
Statistical Methodology.................................................................................................. 84
16.1
Responsibilities..................................................................................................... 84
16.2
Analysis Sets......................................................................................................... 84
16.3
Descriptive Statistics............................................................................................. 84
16.4
Patient Disposition................................................................................................ 85
16.5
Demographics and Baseline Characteristics........................................................... 85
16.6
Recent and Concomitant Medication..................................................................... 85
16.7
Exposure and Compliance..................................................................................... 85
16.8
Efficacy Analyses ................................................................................................. 85
16.8.1
General Efficacy Analysis Methodology................................................. 85
16.8.2
Analysis of the Secondary Endpoints...................................................... 85
16.8.3
Testing Strategy ..................................................................................... 86
16.9
Safety Analyses..................................................................................................... 86
16.9.1
Analysis of Adverse Events.................................................................... 86
16.9.2
Analysis of Other Safety Endpoints........................................................ 86
16.10 Interim Analyses................................................................................................... 86
16.11 Sample Size and Power......................................................................................... 87
16.12 Statistical Analysis Plan ........................................................................................ 87
17
Clinical Study Report and Publications......................................................................... 87
17.1
Data Ownership .................................................................................................... 87
17.2
Clinical Study Report............................................................................................ 87
17.3
Summary of Clinical Study Results ....................................................................... 87
17.4
Publications .......................................................................................................... 87
18
Indemnity and Insurance ............................................................................................... 88
19
Finance............................................................................................................................ 88
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19.1
Site Agreements.................................................................................................... 88
19.2
Financial Disclosure.............................................................................................. 88
19.3
Equipment............................................................................................................. 88
References ............................................................................................................................... 89
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Appendices
Appendix I
Clinical Study Protocol Authentication and Authorisation.............................. 93
Appendix II
Recent and Concomitant Medication Disallowed or Allowed with Restrictions
...................................................................................................................... 95
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List of Panels
Panel 1
Study Design.........................................................................................................12
Panel 2
Study Procedures and Assessments........................................................................13
Panel 3
Objectives and Endpoints......................................................................................31
Panel 4 
IHS ICHD-3 Guidelines for Chronic Cluster Headache..........................................61
Panel 5
Clinical Safety Laboratory Tests............................................................................69
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List of Abbreviations and Definitions of Terms
β-hCG
beta-human chorionic gonadotropin
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
APES
all-patients-enrolled set
APTS
all-patients-treated set
AST
aspartate aminotransferase
ATC
anatomical therapeutic chemical
AUC
area under the curve
BMI
body mass index
cCH
chronic cluster headache
CGRP
calcitonin gene-related peptide
CI
confidence interval
Cmax
maximum observed concentration
COA
clinical outcome assessments
COVID-19
coronavirus disease 2019
CRA
clinical research associate
CRO
Contract Research Organisation
C-SSRS
Columbia-Suicide Severity Rating Scale 
CTFG
Clinical Trials Facilitation and Coordination Group
DNA
deoxyribonucleic acid
DSM-5®
Diagnostic and Statistical Manual of Mental Disorders, fifth edition
EC
ethics committee
ECG
Electrocardiogram
eCRF
electronic case report form
EDTA
ethylenediaminetetraacetic acid
EMA
European Medicines Agency
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQol 5-Dimension 5-Level
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
full-analysis set
GON
greater occipital nerve
HBsAg
hepatitis B surface antigen
HCRU
Health Care Resources Utilization
HCV
hepatitis C virus
HIV
human immunodeficiency virus
ICF
informed consent form
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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
IHS
International Headache Society 
IMP
investigational medicinal product
IND
Investigational New Drug Application
IRB
Institutional Review Board
IRT
interactive response technology
ISR
incurred sample re-analysis
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
Intravenous
LSD
lysergic acid diethylamide
mAb
monoclonal antibody
MMRM
mixed model for repeated measurements
NAb
neutralizing antibody
NOAEL
no-observed-adverse-effect level
NSAID
non-steroidal anti-inflammatory drug
PCR
polymerase chain reaction
PCS
potentially clinically significant
PGIC
Patient Global Impression of Change
PK
pharmacokinetic(s)
PSA
prostate-specific antigen
QP
qualified person
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SFU
safety follow-up
SIS
Sleep Impact Scale
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
t½
terminal-elimination-half-life
TEAE
treatment-emergent adverse event
TMF
trial master file
US FDA
United States Food and Drug Administration
VAS
visual analog scale 
Vc
volume of distribution
WPAI:GH2.0
Work Productivity and Activity Impairment: General Health second version
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Major Changes Since Last Edition
The following summarizes the major changes since the last edition of this CSP.
Chapter/
Section 
Number
Chapter/Section Title
Change
Synopsis
Main Inclusion Criteria
Updated: Inclusion criterion changed from: “The patient has had a 
diagnosis of cluster headache at <50 years of age” to “The patient has 
a medical history of onset of cluster headache ≤50 years of age”.
Synopsis
The following recent and 
concomitant medications 
are disallowed or allowed 
with restrictions prior to or 
during the study (the list is 
not comprehensive)
Steroids (oral and injectable) allowed with restrictions for indications 
other than CH.
3.2
Rationale for the Study 
Design
Added: Clarification that fulfilment of criteria for cCH, according to 
the eligibility criteria in this protocol, will be confirmed via 
prospectively collected information in the eDiary during the screening 
period and the investigator responsibility to review and decide on the 
eligibility of the patient based on data in the eDiary. 
5.3
Selection Criteria
Updated: Inclusion criterion #7 changed from: “The patient has had a 
diagnosis of cluster headache at <50 years of age” to “The patient has 
a medical history of onset of cluster headache at ≤50 years of age”.
8.2.4
Extension of Screening 
Period
Added: Allowance for extension of the screening period if the patient 
does not fulfil Exclusion criterion N°18 and criteria can be met by 
allowing additional 7 days in the Screening period.
8.9
Unscheduled Visits 
Added: Description of unscheduled visits.
9.1.2
Diagnostic Assessments
Added: Definition of an eDiary compliant day has been specified.
Appendix 
II
Recent and Concomitant 
Medication: Disallowed or 
Allowed with Restrictions
Updated: Clarified that cannabinoids are allowed if prescribed or if 
locally approved. Clarified that the maximum dose of lithium must be 
as per the country-specific guidelines for management of patients with 
CH AND the se-lithium level must be below the toxic level based on 
the reference ranges of the local laboratory. Steroids (oral and 
injectable) allowed with restrictions for indications other than CH.
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1
Introduction
1.1
Background
1.1.1
Overview
Chronic cluster headache (cCH) is a rare but disabling primary headache disorder 
characterized by attacks of intense unilateral headache, frequently associated with autonomic 
symptoms such as lacrimation, conjunctival injection, and nasal congestion (International 
Headache Society International Classification of Headache Disorders third edition [IHS 
ICHD-3]).4 The diagnosis of cCH is distinctly recognized and defined by the ICHD-3. The 
natural course of illness of cCH can be conceptualized as cluster headache attacks occurring 
for 1 year or longer without remission, or with remission periods lasting less than 3 months.
The social impact of cluster headache is considerable5 and is associated with considerable 
direct and indirect economic consequences.6 Cluster headache has a prevalence of 0.1% with 
a 2 to 6 times higher average incidence rate for males compared to females.7 However, the 
ratio might be lower due to misdiagnosis of cluster headache in females compared to males.8
The lifetime prevalence of cluster headache, based on a meta-analysis, showed a mean 
prevalence of 124 per 100,000, where episodic form was 6 times more prevalent than the 
chronic form.7
There are significant unmet needs for just about every clinical aspect of cluster headache, 
particularly related to the severity of the disease, the diagnostic challenges and the available 
treatment options. Most patients experiencing cluster headache attacks rate their pain intensity 
as near to or at the worst pain imaginable (using a 10-cm Visual Analog Scale [VAS]).9
The pharmacological armamentarium in cluster headache consists of acute / abortive 
therapies, transitional therapies and preventive treatments. First line of acute treatment is 
sumatriptan administered subcutaneously10, 11, 12 and inhalation of 100% oxygen.13, 14, 15, 16
Transitional therapies are often used to relieve the patient until the preventive agents are 
adequately titrated, and consists of oral steroids or greater occipital nerve (GON) blocks.17, 18
The currently available preventive pharmacological treatments are unspecific, insufficient, 
and hampered by side-effects. Preventive treatment aims to reduce attack frequency with 
verapamil being first-choice, but only 50 to 80% of cluster headache patients are responders;19
and its use is hampered by side-effects since many patients need high doses. Other preventive 
treatments are less attractive due to their side-effect profile, the scarcity of evidence20, 21 and 
high cost.22 In the clinic, several types of treatment are combined in the effort to provide relief 
to the patients and improve the quality of life.
Increased plasma or serum levels of calcitonin gene-related peptide (CGRP) have been 
associated with painful syndromes such as migraine and cluster headache.23 Cluster headache 
patients have higher CGRP levels compared to migraine patients and healthy controls.24 As in 
migraine,25 CGRP levels are altered during attacks. Recently, a provocation study supported 
the central role of CGRP involvement in cluster headache as infusion of CGRP induced 
attacks in patients with cCH and in patients with episodic cluster headache in an active bout.26
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Eptinezumab is a humanised monoclonal antibody (mAb) that inhibits the action of CGRP 
and is approved by the United States Food and Drug Administration (US FDA) as the first 
and only intravenous (IV) preventive treatment for migraine. Results from two 
placebo-controlled, Phase III studies showed that eptinezumab led to a significant reduction in 
the number of monthly migraine days in patients with migraine: both in episodic and chronic 
migraine (study ALD403-CLIN-006,27 and ALD403-CLIN-011,28 respectively). The IV
administration of eptinezumab and its fast onset of action make it a good candidate for 
treatment of patients with cluster headache because an early effect is needed due to the 
relatively short duration and intense severity of the attacks. Cluster headache and migraine 
share some similarities, including the active role of CGRP in the disease biology, and put 
together with the clinical efficacy in migraine, the evidence supports the hypothesis of 
eptinezumab being effective in the treatment of cluster headache.
The following sections 1.1.2 and 1.1.3 provide a brief overview of the nonclinical and clinical 
data currently available for eptinezumab. Refer to the current version of the Investigator’s 
Brochure29 for more detailed information.
1.1.2
Nonclinical Data
Data from the comprehensive program of nonclinical studies support the clinical mechanism 
of action and safety of eptinezumab.
To demonstrate the ability of eptinezumab to block CGRP-driven vasodilation in vivo, several 
primary pharmacodynamic animal studies were conducted in rat, cynomolgus monkey and 
rabbit. The administration of eptinezumab was well tolerated at doses up to 100 mg/kg, the 
highest dose administered, and inhibited increases in dermal blood perfusion induced by 
either topical capsaicin (rats and monkey) or intradermal β-CGRP challenge (rabbit). The 
pharmacodynamic effects were dose-dependent and occurred from 0.1 mg/kg. The 
appropriateness of the nonclinical species has been established in vitro (rat and rabbit). Across 
species (including human), eptinezumab has a binding affinity in the low picomolar range for 
α-and β-CGRP and has been shown to functionally inhibit α-and β-CGRP with high 
specificity.
Intravenous administration of eptinezumab, either as a single- or multiple-dose for 1-month 
duration up to 100 mg/kg/dose in rats or monkeys, or multiple-dose for 6-months duration up 
to 150 mg/kg/dose in monkeys, was well tolerated. No mortality or adverse findings attributed 
to the pharmacological activity of eptinezumab were observed in the single- or repeat-dose 
studies in rats or cynomolgus monkeys. As determined during a 6-month chronic toxicity in 
cynomolgus monkeys, the no-observed-adverse-effect level (NOAEL) of 150 mg/kg/dose 
supports a 103-fold or 123-fold safety margin by maximum observed concentration (Cmax) or 
area under the curve (AUC) for the highest dose, 300 mg, of eptinezumab administered by IV 
infusion every 12 weeks in humans.
Overall, following IV administration in the nonclinical studies, eptinezumab exposure was 
generally dose proportional, and the plasma-concentration profiles were consistent for IV 
administration with the rapid achievement of Cmax followed by a mono-exponential decline.
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The volume of distribution (Vc) for eptinezumab is generally limited to the vascular 
compartment.29
In conformance with applicable guidance documents, a complete package of 
reproductive/development toxicity studies were conducted. In these studies, administration of 
eptinezumab by IV injection to pregnant female rats or rabbits at 75 or 150 mg/kg/dose was 
well tolerated. No effects on male or female reproductive function or performance, fertility or 
early embryonic development in rats were observed. No parental effects or evidence of 
embryo-lethality, fetotoxicity, or teratogenicity in rats or rabbits were observed.
The local tolerance of eptinezumab was assessed following multiple-dose studies in rats and 
cynomolgus monkeys utilizing eptinezumab administered IV. No gross observations 
including erythema and oedema, or toxicologically significant histological changes at the 
injection site(s) were noted in either species for any dose route at concentrations up to 
100 mg/mL eptinezumab.
Biologics in general have minimal risks regarding drug-drug interactions;30 therefore, drug 
interactions with eptinezumab and concomitant medications are not expected, and nonclinical 
studies evaluating the potential for interactions with drugs that may be co-administered with 
eptinezumab were not performed.
1.1.3
Clinical Data
The clinical program of eptinezumab in migraine patients is composed of five completed 
studies to date; including two pivotal placebo-controlled studies (Phase III study in frequent 
episodic migraine [ALD403-CLIN-006],27 and Phase III study in chronic migraine 
[ALD403-CLIN-011]).28 A Phase III study (18903A)31 has been conducted to assess 
treatment of eptinezumab in patients experiencing an acute attack of migraine.
A further global Phase III placebo-controlled study is initiated to evaluate the efficacy and 
safety of eptinezumab in patients with episodic cluster headache (19386A). This study is 
designed to demonstrate a statistically significant effect of eptinezumab on number of attacks 
during the cluster headache bout.
Eptinezumab is administered by IV infusion, which bypasses extravascular absorption routes 
and renders 100% bioavailability. The time required to achieve therapeutic concentrations for 
eptinezumab is rapid and maximum observed Cmax is typically observed at the end of infusion.
The low plasma clearance (0.15 L/d) and protracted terminal-elimination half-life (t½) of 
27 days for eptinezumab support a sustained duration of effect and infrequent, once every 
12 weeks dosing in migraine preventive treatment.
Eptinezumab is not metabolized by cytochrome P450 enzymes. Therefore, interactions by 
eptinezumab with concomitant medications that are substrates, inducers, or inhibitors of 
cytochrome P450 enzymes are considered unlikely.32 Nevertheless, the co-administration of 
eptinezumab in combination with sumatriptan was investigated in Study ALD403-CLIN001.29
The co-administration of sumatriptan did not appear to alter the single dose pharmacokinetic 
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(PK) of eptinezumab. Similarly, the PK of sumatriptan was not impacted upon by the 
co-administration of eptinezumab.
Results from the two pivotal, placebo-controlled, Phase III studies showed that eptinezumab 
at doses of 100 mg or 300 mg administered by IV infusion every 12 weeks (2 infusions) led to 
significant reductions in monthly migraine days in patients with episodic or chronic migraine 
(ALD403-CLIN-006 and ALD403-CLIN-011).27, 28 Both eptinezumab 300 mg and 100 mg 
groups achieved the primary efficacy endpoint and all key secondary endpoints in the 
prespecified statistical hierarchy. The therapeutic benefit resulting from administration of 
eptinezumab for the preventive treatment of migraine in adults is robust and clinically 
meaningful, as demonstrated by the results of the 75% and 50% migraine responder analyses. 
Administration of eptinezumab 100 or 300 mg resulted in a rapid, migraine preventive effect 
that was established on the day after the first infusion and maintained over the 12-week 
dosing cycle. Both eptinezumab doses were associated with a consistent pattern of statistically 
significant and clinically meaningful efficacy across these endpoints compared with placebo.
The safety of eptinezumab has been evaluated in more than 2,400 subjects in doses up to 
1000 mg. Long-term data with eptinezumab is limited; however, in study ALD403-CLIN-013 
a total of 100 patients have been treated with the 300 mg dose and completed the study at 
Week 104 and no new significant findings have been identified during the long-term 
follow-up. In patients with migraine, nasopharyngitis and hypersensitivity reactions, including
anaphylactic reactions, are considered adverse drug reactions for eptinezumab. In the pivotal 
Phase III studies (ALD403-CLIN-006 and ALD403-CLIN-011) hypersensitivity reactions 
were reported with multiple related adverse event terms, such as hypersensitivity, 
angioedema, urticaria, flushing/hot flush, rash and pruritus. These events were reported in 
approximately 4% of patients on 300 mg eptinezumab, 3% of patients on 100 mg 
eptinezumab and 1% of patients on placebo. Serious hypersensitivity reactions have been 
reported, including anaphylactic reactions on rare occasions. In most cases, the events 
developed during or within minutes of the infusion and subjects recovered following drug 
discontinuation and adequate treatment.
The safety findings to date indicate that eptinezumab is well tolerated and demonstrates a 
favourable risk-benefit profile based on review of nonclinical, clinical, and scientific literature 
data.
1.2
Rationale for the Study
Cluster headache is an excruciatingly painful primary headache disorder, which places an 
exceptional burden on those affected. Few, if any, medical disorders are more painful than 
cluster headache. Patients describe the pain of a single attack as being worse than anything 
else they have experienced. The severity of the pain has earned it the sobriquet “suicide 
headache”. Most patients with cluster headache have suicidal thoughts, but relatively little 
have self-harmful behaviour.33
There are significant unmet needs for just about every clinical aspect of the patient with 
cluster headache, particularly related to the severity of the disease and treatment options. Most 
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patients experiencing cluster headache attacks rate their pain intensity as near to or at the 
worst pain imaginable (using a VAS).9
Due to the high unmet need for new, effective, fast onset and better tolerated therapies for
cluster headache, Lundbeck is planning to conduct a study in order to evaluate the long-term 
treatment with eptinezumab in patients with cluster headache. The study will evaluate, in an 
open-label design, the potential of eptinezumab to reduce the number of cluster headache 
attacks and severity of pain in a population of patients with cCH. The study will also provide 
supportive data to the ongoing Phase III study on the efficacy of eptinezumab in episodic 
cluster headache (19386A), to demonstrate that eptinezumab is a safe therapeutic option for 
cluster headache. The results from a Phase III study with galcanezumab in episodic cluster 
headache,43 and its approval by the US FDA in this indication, prove the principle that mAbs, 
targeting CGRP, can be beneficial in cluster headache. Thus eptinezumab, which has similar 
biological properties and a faster onset of action in patients with migraine, is considered a 
viable therapeutic option to alleviate the symptoms of the disease in patients with cluster 
headache.
2
Objectives and Endpoints
The study objectives and endpoints are summarised in Panel 3.
Panel 3
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To evaluate the long-term safety and 
tolerability of eptinezumab in patients with 
cCH
Endpoints for the primary objective:
adverse events
absolute values and changes from baseline in clinical 
safety laboratory test values, vital signs, weight, and 
electrocardiogram (ECG) parameter values
potentially clinically significant (PCS) clinical safety 
laboratory test values, vital signs, weight changes, and 
ECG parameter values
development of specific anti-eptinezumab antibodies 
(ADA), including neutralizing antibodies (NAbs)
Columbia-Suicide Severity Rating Scale (C-SSRS) score
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Secondary Objectives
To evaluate the efficacy of eptinezumab in 
patients with cCH 
Endpoints for the secondary objective (efficacy):
Conversion from cCH to episodic cluster headache
(Week 0 to Week 48): Number of patients with no cluster 
headache attacks for ≥3 consecutive months 
(≥13 consecutive weeks)
Change from baseline in weekly number of times an 
abortive therapy (oxygen and/or triptans) was used 
(calculated for each infusion with eptinezumab, taking the 
average across the first 4 weeks after the infusion)
Change from baseline in the average number of weekly 
attacks (calculated for each infusion with eptinezumab, 
taking the average across the first 4 weeks after the 
infusion)
Change from baseline in the 5-point self-rating pain 
severity scale (calculated for each infusion with 
eptinezumab, taking the average across the first 4 weeks 
after the infusion)
Response: ≥30% reduction in number of weekly attacks 
(calculated for each infusion with eptinezumab, based on 
the average across the first 4 weeks after the infusion)
Response: ≥50% reduction in number of weekly attacks 
(calculated for each infusion with eptinezumab, based on 
the average across the first 4 weeks after the infusion)
cCH remission (Week 0 to Week 48): Number of patients 
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks)
cCH remission (Week 0 to Week 12): Number of patients 
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks between the first and second 
infusion)
cCH remission (Week 12 to Week 24): Number of patients 
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks between the second and third 
infusion)
cCH remission (Week 24 to Week 36): Number of patients 
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks between the third and fourth 
infusion)
cCH remission (Week 36 to Week 48): Number of patients 
with no cluster headache attacks for ≥1 month 
(5 consecutive weeks within the first 12 weeks after the 
fourth infusion)
Number of patients who received a transitional therapy 
during the Treatment Period (Week 0 to Week 48)
Patient Global Impression of Change (PGIC) score 
(assessed monthly after the first eptinezumab infusion)
Change from baseline in Sleep Impact Scale (SIS) domain 
scores (at each infusion and 4 weeks after each infusion)
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Secondary Objectives (continued)
To evaluate the efficacy of eptinezumab in 
patients with cCH (continued)
Exploratory endpoints for the secondary objective 
(efficacy):
Change from baseline in the average number of monthly 
attacks (per 4-week intervals after each eptinezumab 
infusion)
Change from baseline in the 5-point self-rating pain 
severity scale (taking the average across 4-week intervals 
after each eptinezumab infusion)
Response: ≥30% reduction in number of monthly attacks 
by 4-week intervals after each eptinezumab infusion, and 
for each of the periods between infusions with 
eptinezumab, and for 12 weeks after the last eptinezumab 
infusion
Response: ≥50% reduction in number of monthly attacks 
by 4-week intervals after each eptinezumab infusion, and 
for each of the periods between infusions with 
eptinezumab, and for 12 weeks after the last eptinezumab 
infusion
Response: 100% reduction in number of monthly attacks 
by 4-week intervals after each eptinezumab infusion, and 
for each of the periods between infusions with 
eptinezumab, and for 12 weeks after the last eptinezumab 
infusion
Change from baseline in monthly number of times an 
abortive therapy (oxygen and/or triptans) was used (per 
4-week interval after each eptinezumab infusion)
To evaluate the efficacy of eptinezumab on 
health-related quality of life, health care 
resource utilization, and work productivity
Endpoints for the secondary objective:
Change from baseline in EuroQol 5-Dimension 5-Level 
(EQ-5D-5L) at Weeks 4, 16, 28, 40 and 48
Health Care Resources Utilization (HCRU) at baseline, 
Weeks 4, 16, 28, 40 and 48
Change from baseline in the Work Productivity Activity 
Impairment: General Health second version 
(WPAI:GH2.0) sub-scores (Absenteeism, Presenteeism, 
Work productivity loss, Activity impairment) at Weeks 4, 
16, 28, 40 and 48
Exploratory Objective
To explore the target engagement of 
eptinezumab to CGRP
Endpoint for the exploratory objective:
Change from baseline to each study time point in CGRP: 
CGRP-eptinezumab complex, free CGRP
3
Study Design
3.1
Overview of the Study Design
This study has been designed in accordance with the Declaration of Helsinki.34
This is an interventional, open-label, fixed-dose multiple administration study to evaluate the 
long-term treatment with eptinezumab in patients with cCH.
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This study will be conducted in compliance with the protocol, Good Clinical Practice,35 and 
applicable regulatory requirements.
An overview of the study design is presented in Panel 1.
The target population for this study is defined as patients with cCH, based on the IHS ICHD-3 
classification,4 with documented evidence of cCH prior to screening and confirmed via 
prospectively-collected information in the eDiary during the Screening Period.
The total study duration from the Screening Visit to the Safety Follow-up (SFU) Visit is 
approximately 60 weeks and includes Screening Period (4 weeks), Treatment Period 
(48 weeks), and SFU Period (8 weeks).
Eligible patients will receive four infusions with eptinezumab 400 mg at 12-week intervals at 
Day 0 (Visit 2), at the end of Weeks 12 (Visit 5), 24 (Visit 8) and 36 (Visit 11), administered 
as an IV infusion over 45 minutes (+15 minutes).
The SFU Visit will take place at Week 56 (Visit 15) that is 20 weeks (5 half-lives) after the 
last eptinezumab administration.
Patients who withdraw from the study, except for those who withdraw their consent, will be 
asked to attend a Withdrawal Visit as soon as possible and a further SFU Visit, scheduled 
20 weeks (5 half-lives) after the last eptinezumab administration.
Patients who are withdrawn from the treatment will be given the opportunity to remain in the 
study at the discretion of the investigator. Patients will be expected to attend all scheduled 
study visits and procedures except eptinezumab administration. If patients refuse, they will be 
asked to attend a Withdrawal Visit as soon as possible and a further SFU Visit, scheduled 20 
weeks (5 half-lives) after the last eptinezumab administration.
Eligibility will be assessed during the Screening Period and before the first administration of 
eptinezumab at Day 0 (Visit 2) as described in Panel 2.
The following visits will be site visits: Screening Visit at Week -4 (Visit 1), Investigational 
Medicinal Product (IMP) Visits at Weeks 0, 12, 24 and 36 (Visits 2, 5, 8 and 11), Completion 
Visit at Week 48 (Visit 14) and SFU Visit at Week 56 (Visit 15) or Withdrawal Visit, if 
applicable. All other study visits will be phone contact visits.
In exceptional situations to be approved by the Contract Research Organisation’s (CRO)
medical monitor, site visits may only consist of blood and urine sampling (for clinical safety 
laboratory tests, exploratory eptinezumab quantification, ADA including NAb, and 
exploratory biomarkers), ECG, vital signs, physical and neurological examinations, adverse 
events recording, and eptinezumab administration, while the remaining assessments (eDiary, 
electronic patient-reported outcomes [ePROs], C-SSRS, and investigator evaluations) can be 
conducted remotely as virtual clinic visits in line with the US FDA and European Medicines 
Agency (EMA) guidances.36, 37
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Patients will be assigned an eDiary at the beginning of the Screening Period (Visit 1, 
Week -4) and will be required to complete it:
Daily - during the Screening Period (from Week -4 to Day 0) and during the first 4 weeks 
that follow each eptinezumab infusion (Weeks 1 to 4, 13 to 16, 25 to 28, and 37 to 40).
Weekly - for Weeks 5 to 12, 17 to 24, 29 to 36, and 41 to 48.
During the study visits with eptinezumab infusion, eDiary and ePROs must be completed 
prior to infusion and prior to any interaction with the clinical site staff.
At these visits, safety assessments will be performed before and after the infusion. Safety 
assessments before eptinezumab infusion consists of vital signs (including body temperature),
weight, concomitant medications, adverse events (AEs), ECG, blood sampling (for clinical 
safety laboratory tests, exploratory eptinezumab quantification, and ADA including NAb), 
urine sampling (for clinical safety laboratory and pregnancy tests) and C-SSRS. Safety 
assessments after eptinezumab infusion consists of vital signs including body temperature, 
and adverse events.
Blood samples for exploratory eptinezumab quantification, and ADA and NAbs assessments 
will be collected at regular intervals during the study (Panel 2) and results will be reported 
separately.
Patients in the study will have access to appropriate medical care in accordance with normal 
clinical practice after they complete or withdraw from the study.
Assessments performed in a subset of patients:
Blood sampling for pharmacogenetics is optional. Refer to Panel 2.
3.2
Rationale for the Study Design
The current study is planned as fixed-dose, multiple infusions study with an open-label 
design. The duration of the Treatment Period is chosen to allow generation of long-term 
exposure safety and tolerability data in patients with cCH, upon multiple infusions with 
eptinezumab 400 mg. The duration of the Screening Period is chosen to inform on the 
baseline disease activity in a population of patients with cCH who are managed according to 
the established standards of care.
The proposed study population are patients with cCH. Episodic cluster headache and cCH 
share common pathophysiology and overlapping clinical symptoms with the major 
differences between the two forms of cluster headache residing in the duration of the “active” 
and “remission” periods and, very important from a clinical point of view, patients with cCH 
have a very poor response to preventive medications.38 The distinctions in two separate forms 
is, in some cases, solely virtual as when exacerbations lengthen, remissions shorten or more 
clusters occur than usual, the sufferers might be switching from episodic to chronic cluster 
headache.39 Unhealthy lifestyle factors like smoking, alcohol overuse and high body mass 
index (BMI) are common for patients with episodic cluster headache and cCH and several 
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lifestyle related diseases like metabolic disease, gastric ulcer, menstrual diseases in women 
and visual disorders are being more frequently reported in cCH than in episodic cluster 
headache.40 Therefore 1-year exposure to eptinezumab of patients with cCH, is considered an 
acceptable conservative approach to generate safety and tolerability data to adequately 
support the data, generated in the ongoing Phase III study in episodic cluster headache
sufferers (19386A). In addition, the patients with cCH are the patient population, in need for 
long-term treatment to alleviate the symptoms of cluster headache.
As the current study will provide long-term safety data to support data from the ongoing 
Phase III study in episodic cluster headache sufferers (19386A), the same dose of 400 mg 
eptinezumab will be administered in both studies. This dose has been selected based on the 
fact that cluster headache patients have higher CGRP levels compared to migraine patients 
and healthy controls24, and a higher frequency of attacks compared to patients with migraine, 
suggesting that a higher dose of eptinezumab compared to the dose(s) approved for migraine 
prevention, is needed to alleviate features of the disease, related to the CGRP pathobiology. 
This together with PK and safety data from the completed Phase I studies in the migraine 
program,29 in which eptinezumab was dosed up to 1000 mg and without any major safety 
findings, support that eptinezumab 400 mg can be safely used in the current study. This is in 
line with the dose considerations in the galcanezumab study in episodic cluster headache43
which investigated the efficacy and safety of a dose which is almost three-folds the 
galcanezumab dose recommended for the treatment of migraine.41, 42
Fulfilment of criteria for cCH, according to the eligibility criteria in this protocol, will be 
confirmed via prospectively collected information in the eDiary during the screening period,
that is CH attack frequency of minimum 14 CH attacks for the 28-day Screening Period. The 
lower limit for CH attack frequency is in line with the IHS ICHD-3 criteria for CH. Clinical 
site staff will be given access to the eDiary data. Prior to enrolment, the investigator will 
review the data in the eDiary Eligibility Report to determine if the eligibility criteria are 
fulfilled.
Due to the high dose administered, the infusion time of eptinezumab is increased to 
45 minutes in order to minimize the potential risk of hypersensitivity reactions associated 
with biologics.44
All patients will receive four infusions of eptinezumab 400 mg at 12-week intervals. Given 
the eptinezumab half-life and proven efficacy over 12 weeks in migraineurs, it is considered 
that all patients will be exposed to eptinezumab for a period of approximately 1 year. 
Abortive and preventive treatments, as well as transitional therapies are allowed, or allowed 
with restrictions, during the study, hence no patient will be denied access to standard 
treatments.
The sample size is chosen to support assessment of the safety and tolerability of long-term 
exposure to eptinezumab in patients with cluster headache. The number of patients treated 
will ensure that a sufficient number of patients will have been treated for 1 year, so the 
long-term exposure safety and tolerability of eptinezumab 400 mg can be assessed.1
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The mean change from baseline in the number of cluster headache attacks is included to 
assess whether a symptom reduction is seen. This matches the primary endpoint from the 
ongoing placebo-controlled study in episodic cluster headache (19386A), which is the change 
from baseline in number of weekly attacks (Weeks 1–2), evaluated at Week 2. Secondary 
endpoints evaluating sleep disturbances, health-related quality of life, as well as work 
productivity, are included in the study to evaluate the treatment effect beyond the reduction in 
number of cluster headache attacks.
Blood sampling will be required at several time points during the study to evaluate standard 
safety laboratory parameters, ADA including NAbs.
3.3
Benefit-Risk Assessment
Benefits
It has been shown that mAbs targeting CGRP provide clinical benefit in patients with episodic 
cluster headache.43 Therefore, eptinezumab, which is also a mAb targeting CGRP with 
documented fast onset of action in patients in need of preventive treatment for migraine, is 
considered a viable therapeutic option to provide a fast reduction in the number of cluster 
headache attacks in patients with cCH. The intravenous formulation offers a route of 
administration with 100% bioavailability that allows for rapid CGRP inhibition.
Risks
No safety data, specific to the use of eptinezumab in patients with cluster headache is 
available. However, the safety of eptinezumab has been investigated in over 2,400 healthy 
subjects and patients with migraine at doses up to 1000 mg and the analyses show that 
eptinezumab is safe and well tolerated (see the current version of the Investigator’s 
Brochure29 for more detailed information). No important identified risks or important 
potential risks that could alter the benefit-risk profile of eptinezumab have been identified to 
date. Nasopharyngitis and hypersensitivity reactions, including anaphylactic reactions, are 
considered adverse reactions for eptinezumab. In the pivotal studies in migraine, 
hypersensitivity reactions were reported with multiple related adverse event terms, such as 
hypersensitivity, angioedema, urticaria, flushing/hot flush, rash and pruritus. Most 
hypersensitivity reactions occurred during the infusion and were not serious. Serious 
hypersensitivity reactions have been reported, including anaphylactic reactions on rare 
occasions. In all cases, the patients recovered upon standard of care treatment.
With regard to the safety of the eptinezumab 400 mg dose, the safety of eptinezumab in 
patients with migraine and in healthy subjects has been explored at doses up to 1000 mg, with 
no observable difference in the safety profile compared to the eptinezumab 100 mg and 
300 mg doses, which are the doses approved by the US FDA and in Canada for preventive 
treatment of migraine. In addition, the treatment effect and safety of eptinezumab 400 mg is 
currently being investigated in patients with episodic cluster headache in an ongoing pivotal 
study (19386A).
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The safety of study subjects is monitored throughout the study via periodic collection of 
adverse events, vital signs, laboratory tests, ECGs and other safety assessments such as 
evaluation of the suicidality (C-SSRS). Although there was no evidence of impact of ADA 
development on efficacy or safety in any of the previous clinical studies, in the current study 
blood sampling for ADA including NAbs will be assessed prior to the first eptinezumab 
infusion, at Weeks 12, 24, 36, 48 and 56 (Safety Follow-up), and at Withdrawal Visit when 
applicable. To monitor patient safety, safety data will be reviewed on an ongoing basis and 
evaluated regularly by the Lundbeck Safety Committee. This will ensure that prompt actions 
are taken, if needed.
Risk-mitigation
Based on the biological plausibility and the inherent risk, hypersensitivity reactions are 
possible with any infused protein.44 In order to minimize the risk of hypersensitivity reactions 
due to the higher dose of eptinezumab (400 mg considered justified in patients with cluster 
headache based on the higher CGRP levels) compared to doses used in migraine (100 mg or 
300 mg), the minimum duration of the eptinezumab infusion must be 45 minutes 
(45 + 15 minutes, according to the study protocol).
Furthermore, eptinezumab is administered in a clinical facility at the study site under medical 
supervision with appropriate measures for adequate treatment in place. Per protocol, patients 
are required to be monitored during the infusion and for a period of 1 hour from the 
end-of-infusion. Patients will be requested to stay longer should the investigator determine 
this is clinically warranted.
In addition to the above, the following risk mitigations are also taken for hypersensitivity 
reactions:
History of severe drug allergy or hypersensitivity or known hypersensitivity to 
IMP/excipients is an exclusion criterion.
Serious/severe hypersensitivity is a criterion for withdrawal from treatment.
In the context of the coronavirus disease 2019 (COVID-19), Lundbeck and the CRO will 
continue to follow each participating country’s guidance for travel, social distancing, 
minimum number of people in an indoor location at any time, personal protective equipment, 
and remote consenting procedures. Should further restrictions be imposed in any country that 
could impact patients’ ability to attend visits, and/or clinical site staff’s ability to continue to 
resource the study to an adequate level, Lundbeck and the CRO will adapt their approach to 
patient enrolment and return visits. These mitigations will include, but not limited to:
Including a home nursing vendor to ensure the continuation of IMP Visits, including 
eptinezumab administration and post-infusion monitoring (if logistically possible and 
acceptable by the country-specific law). The administration via the home nursing vendor 
will have the same medical supervision and equipment/treatment in place needed to ensure 
patient’s safety as similar to the clinical facility at the study site.
Risk assessment (per country or site level) of enrolling new patients.
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Benefit-Risk Assessment
Cluster headache is an excruciatingly painful primary headache disorder, which places an 
exceptional burden on those affected. There are significant unmet needs for the patient with 
cluster headache, particularly related to the severity of the disease and the lack of available 
fast onset, and better tolerated therapies.
The safety of eptinezumab, as investigated in patients with migraine and in healthy 
volunteers, shows that eptinezumab is safe and well tolerated. The risks for study subjects are 
further mitigated by measures in the protocol and safety monitoring of study subjects 
throughout the study.
H. Lundbeck A/S considers the benefit-risk profile of Study 19385A to be acceptable based 
on the nonclinical and clinical data for eptinezumab.
4
Ethics
4.1
Ethical Rationale
This study will evaluate the long-term safety and tolerability of eptinezumab in patients with 
cCH.
The dose of 400 mg eptinezumab is selected, based on the fact that cluster headache patients 
have higher CGRP levels compared to migraine patients and healthy controls24, suggesting 
that a higher dose of eptinezumab is needed to alleviate features of the disease, related to the 
CGRP pathobiology. The published results of the galcanezumab study in episodic cluster 
headache43 which investigated the efficacy and safety of a dose, higher, compared to the 
approved galcanezumab dose for the treatment of migraine do not suggest any safety concerns 
and provide further support for the dose selection.41, 42
The patients will be fully informed about the study, including the risks and benefits of their 
participation in the study.
The patient may withdraw from the study at any time, for any reason, specified or unspecified 
and without penalty or loss of benefits to which the patient is otherwise entitled. Unscheduled 
visits can be made, and immediate withdrawal is possible. Throughout the study, signs of 
suicidal risk will be assessed and the patients at risk will be withdrawn from the study.
In general, safety data with eptinezumab have not raised any clinical safety concerns from the 
completed Phase III studies in migraine. However, it cannot be ruled out that eptinezumab
could have adverse effects that have not yet been reported. Blood sampling will be required at 
several time points during the study to evaluate standard safety laboratory parameters. 
Although there was no evidence of impact of ADA development on efficacy or safety in any 
of the previous clinical studies, in the current study the ADA response will be assessed prior 
to the first eptinezumab infusion and, at Weeks 12, 24, 36, 48 and 56 (SFU), and at 
Withdrawal Visit when applicable.
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The risks associated with this study are considered adequately elucidated in the nonclinical 
and clinical studies, well controlled by cautionary measures in the study design, and 
well-balanced with the potential benefits of the treatment with eptinezumab, a potentially safe 
and effective treatment for episodic cluster headache.
In accordance with Good Clinical Practice,35 qualified medical personnel at Lundbeck or the 
CRO will be readily available to advise on study-related medical questions. Medical 
monitoring will be performed throughout the study. Safety data will be reviewed regularly by 
the Lundbeck Safety Committee to ensure that prompt action is taken, if needed.
In accordance with Good Clinical Practice,35 the investigator will be responsible for all 
study-related medical decisions.
Information on race will be collected, if allowed according to the country-specific law. 
Collecting information on race will allow the evaluation of treatment effects including safety 
evaluations in the overall population as well as investigations of the potential impact of 
intrinsic and extrinsic factors (as described in Ethnic Factors in the Acceptability of Foreign 
Clinical Data ICH E5(R1) Guideline).45
Risks Related to the Coronavirus Disease 2019
Lundbeck and the CRO have performed a review of the protocol, the participant population, 
and study design and conclude that the risks with regards to the COVID-19 are minimized 
both for patients participating in the study and clinical site staff conducting the study in line 
with the US FDA and EMA guidances.36, 37 The risks for the patients remain well controlled 
and balanced with the potential benefits of the treatment. This is based on the following:
Patients participating in the clinical study will not attend visits in an area of the hospital 
that would be high risk for COVID-19 patients to be treated or seen.
The protocol has flexibility for re-screening and Screening Period extension to further 
enable sites and patients to continue the study in case of quarantine or lockdowns.
Patient visits to site will be limited to seven on site visits over a time span of 60 weeks and 
all further contact will be conducted by phone. In exceptional situations to be approved by 
the CRO’s medical monitor, site visits may only consist of blood and urine sampling (for 
clinical safety laboratory tests, exploratory eptinezumab quantification, ADA including 
NAb, and exploratory biomarkers), ECG, vital signs, physical and neurological 
examinations, adverse events recording, and eptinezumab administration, while the 
remaining assessments (eDiary, ePROs, C-SSRS, and investigator evaluations) can be 
conducted remotely via a virtual clinic visit. Consequently, this reduces the burden on the 
clinical site to manage recurring visits around the potential restrictions for number of 
people allowed on site at any one time.
Study allows the flexibility at Screening Visit to allow for review and signature of 
Informed Consent Form(s) via virtual clinic visit and Screening Visit assessments may be 
extended over several days, if needed. For other visits, patients are allowed to complete 
eDiary and ePROs in the remote setting (that is, at home), thus reducing the time that the 
patient needs to spend on site and minimizing burden for clinical site staff at a given visit.
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The percentage of onsite targeted source data verification required for the study is 
approximately 30%, which, along with the number of visits for this study, substantially 
decreases the amount of time clinical research associates (CRAs) are expected to spend on 
site. Further, remote source data verification is allowed in some cases as described in 
section 12.
Lundbeck and the CRO will continue to follow each participating country’s guidance for 
travel, social distancing, minimum number of people in an indoor location at any time, 
personal protective equipment, and remote consenting procedures. Should further restrictions 
be imposed in any country that could impact patients’ and CRAs’ ability to attend visits, 
and/or clinical site staff’s ability to continue to resource the study to an adequate level, 
Lundbeck and the CRO will adapt their approach to patient enrolment, return visits and data 
monitoring by CRAs. These mitigations will include, but not limited to:
Including a home nursing vendor to ensure the continuation of IMP Visits (if logistically 
possible and acceptable by the country-specific law). The administration via the home 
nursing vendor will have the same medical supervision and equipment/treatment in place 
needed to ensure patient’s safety as similar to the clinical facility at the study site.
An adaptation of the onsite data monitoring scheme to increase remote monitoring and 
consideration of remote source data verification.
Risk assessment (per country or site level) of enrolling new patients.
Any adaptations to the already approved protocol procedures and monitoring approach will be 
implemented in in line with the US FDA and EMA guidances.36, 37
Lundbeck and the CRO will assess on a site-by-site basis whether restrictions, either at a 
country or site level, would mean it would not be within the best interest of the potential 
patient or the clinical site staff to activate the clinical site at a particular time point. This 
would be based on, but not limited to, the following:
Country/area lockdowns.
A site’s ability to undertake non-essential clinic visits.
A site’s ability to adequately resource the study.
CRO-implemented restrictions for employee safety for travel and onsite visits.
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.
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 clinical site delegation log.
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At the Screening Visit, the patient will be asked to sign the:
Main Informed Consent Form (ICF);
Informed Consent Form for blood sampling for pharmacogenetics (optional).
Depending of the country requirements, the number of ICFs may be different.
In case of pregnancy, and if required by local regulations, the patient and her partner will be 
asked to sign a separate Informed Consent Form. For country-specific pregnancy Informed 
Consent Form, refer to section 10.2.
Under exceptional circumstances, the discussion with the patients about the Informed Consent 
Form(s) can be done as a virtual clinic visit and the Informed Consent Form(s) can be 
provided remotely in line with the US FDA and EMA guidances.36, 37 According to the EMA 
guidance, this could comprise contacting the patients via phone or video-calls and obtaining 
oral consents, to be documented in the patients' medical records, supplemented with email 
confirmation. Any consent obtained this way should be documented and confirmed by way of 
normal consent procedures at the earliest opportunity when the patients are back at the clinical 
sites.37
Re-screening of the Screening Visit is allowed under certain circumstances. Refer to 
section 8.2.3.
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. Vulnerable patients include pregnant and 
breastfeeding women, minors, patients that cannot read and understand the Informed Consent 
Form(s), patients hospitalised without consent or deprived of liberty due to legal or 
administrative decision, as well as patients under legal guardianship and unable to provide 
their consent.
Prior to obtaining written informed consent, the investigator or a designee must explain to the 
patients the aims and methods of the study and any reasonably expected benefits and 
foreseeable risks or inconveniences to the patients.
The patients must be informed:
that their participation in the study is voluntary and that they are free to withdraw from the 
study at any time without justifying their decision;
of the possibility of withdrawing consent (section 8.7);
of the possibility to remain in the study even after treatment withdrawal (that is to attend 
all visits and perform all procedures except eptinezumab administration);
of their right to request a copy of their personal data from the study via the investigator;
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.
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The patients must be informed that persons authorised by Lundbeck and authorised personnel 
from certain authorities (domestic, foreign, data protection agencies, or ethics committee
[ECs] or Institutional Review Board [IRBs]) may view their medical records. The patients 
must also be informed that de-personalized copies of parts of their medical records may be 
requested by authorised personnel from certain authorities (domestic, foreign, data protection 
agencies, or ECs or IRBs) for verification of study procedures and/or data. The confidentiality 
of the patients will in all cases be respected.
The patients must be given ample time and opportunity to enquire about details of the study 
prior to deciding whether to participate in the study.
It is the responsibility of the investigator to ensure that all questions about the study are 
answered to the satisfaction of the patients. Prior to allowing a patient to participate in the 
study, an Informed Consent Form must be signed and dated by the patient and signed and 
dated by the investigator or a designee on the same day. The patients must be given a copy of 
the written information (Patient Information Sheet) as well as a copy of the signed Informed 
Consent Form(s).
The consent procedures described above will only be implemented if allowed by local law 
and regulations and will only be initiated after approval by the relevant ECs or IRBs.
As the blood sampling for the exploratory gene expression profiling (ribonucleic acid [RNA]), 
metabolomic and proteomic analyses, including blood sampling for exploratory eptinezumab
quantification, ADA biobanking and exploratory biomarkers, is an integral part of this study, 
the main Informed Consent Form covers these analyses. Conversely, the blood sampling for 
pharmacogenetics is optional and a separate Informed Consent Form covers this analysis.
The blood samples for potential future exploratory analysis, or the data derived from these 
blood samples, may be shared with academic and public institutions and other companies. 
However, Lundbeck will retain full control of the samples and their use in accordance with 
the information in the Informed Consent Form and a Material Transfer Agreement.
A patient may, at any time and without stating a reason, specifically request the destruction of 
the patient’s deoxyribonucleic acid (DNA) sample, irrespective of the patient’s continued 
participation in the study. The investigator must send a written request on behalf of the patient 
to the international study manager. The investigator will receive written confirmation from 
Lundbeck when the DNA sample has been destroyed.
4.3
Personal Data Protection
The data collected in this study will be processed in accordance with the specifications 
outlined in the Danish Data Protection Act and the European Union legislation46 to ensure that 
requirements regarding personal data protection are met. If an external organisation will 
process data on behalf of Lundbeck, a contractual procedure will be signed between 
Lundbeck or delegate and the external organisation to ensure compliance with the above-
mentioned legislation.
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4.4
Ethics Committees and Institutional Review Boards
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.
5
Study Population
5.1
Number of Patients and Regions
Planned regions: 
Europe and North America
Planned number of screened patients (approximately): 
200
Planned number of enrolled patients:
125
5.2
Patient Recruitment
Competitive patient recruitment between sites will be used during the entire recruitment 
period to ensure that the required number of patients are enrolled 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 and none of the exclusion criteria at the 
Screening Visit and Baseline Visit (Day 0/Visit 2) are eligible to participate in this study.
Inclusion Criteria
1.
The patient is able to read and understand the Informed Consent Form(s).
2.
The patient has signed the Informed Consent Form(s).
3.
The patient is willing and able to attend study appointments within the specified time 
windows.
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4.
The patient is an outpatient.
5.
The patient has adequate venous access for administration of study drug.
6.
The patient has a diagnosis of cCH as defined by IHS ICHD-3 classification4 (see 
section 9.1.2) with a history of cCH of at least 12 months prior to the Screening Visit.
7.
The patient has a medical history of onset of cluster headache at ≤50 years of age.
8.
The patient has an adequately documented record of previous abortive, transitional and 
preventive medication use for cCH, for at least 12 months prior to the Screening Visit.
9.
The patient is able to distinguish cluster headache attacks from other headaches (such as
tension-type headaches, migraine).
10. The patient has during the Screening Period, based on prospectively collected 
information in the eDiary, a cluster headache attack frequency of (this requirement 
should not be shared with the patient):
minimum 14 cluster headache attacks for the 28-day Screening Period
11. The patient has demonstrated compliance with the eDiary by entry of data for at least 
24 out of 28 days during the 4-week Screening Period.
12. The patient is aged ≥18 and ≤75 years at the Screening Visit.
13. The patient, if a woman, must:
have had her last natural menstruation ≥12 months prior to the Screening Visit, OR
have been surgically sterilized prior to the Screening Visit, OR
have had a hysterectomy prior to the Screening Visit, OR
remain sexually abstinent, when this is in line with her preferred and usual lifestyle, OR
engage exclusively in same-sex relationships, OR
agree not to try to become pregnant during the study, AND
use at least one of the below adequate contraception:*,47
combined oral, intravaginal or transdermal hormonal contraception
progestogen-only oral, injectable or implantable hormonal contraception
intrauterine devices (IUD)
intrauterine hormone-releasing system (IUS)
barrier methods (such as male or female condom) with spermicide
vasectomized partner
The contraception must be used from the Screening Visit to ≥6 months after the last 
dose of eptinezumab.
* In line with the Clinical Trials Facilitation and Coordination Group’s (CTFG) guidance document 
on “Recommendations related to contraception and pregnancy testing in clinical trials” (2020) and 
based on the available non-clinical and clinical data for eptinezumab, the risk of human 
teratogenicity/fetotoxicity for eptinezumab is considered unlikely. Therefore, in accordance with 
the CTFG guidance document, the use of at least an acceptable effective contraceptive measure is 
required for woman of child-bearing potential for a compound like eptinezumab and no 
contraception measures are needed for male patients.
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14. The patient, if a woman of childbearing potential, must have a confirmed negative blood 
pregnancy test at the Screening Visit and a confirmed negative urine pregnancy test at the 
Baseline Visit.
Exclusion Criteria
1.
The patient has previously been enrolled in this study and has received at least one 
eptinezumab infusion.
2.
The patient has experienced failure on a previous treatment targeting the CGRP pathway 
(anti-CGRP mAbs and gepants).
3.
The patient has participated in a clinical study <30 days or has taken any investigational 
products within 5 plasma half-lives (whichever is longer) prior to the Screening Visit.
4.
The patient is a member of the study personnel or of their immediate families, or is a 
subordinate (or immediate family member of a subordinate) to any of the study 
personnel.
5.
The patient is pregnant or breastfeeding.
6.
The patient has a history of severe drug allergy or hypersensitivity, or known 
hypersensitivity or intolerance to the IMP or its excipients.
7.
The patient has confounding and clinically significant pain syndromes (for example, 
fibromyalgia, complex regional pain syndrome).
8.
The patient has a history or diagnosis of chronic paroxysmal hemicrania.
9.
The patient has a history or diagnosis of chronic tension-type headache, hypnic headache, 
hemicrania continua, new daily persistent headache, chronic migraine or unusual 
migraine subtypes such as hemiplegic migraine (sporadic and familial), recurrent painful 
ophthalmoplegic neuropathy, migraine with neurological accompaniments that are not 
typical of migraine aura (diplopia, altered consciousness, or longer than 1 hour).
10. Patients with a history of epilepsy.
11. Patients with 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 the Screening Visit.
12. The patient has a current diagnosis or history of substance abuse or alcohol abuse 
(Diagnostic and Statistical Manual of Mental Disorders, fifth edition [DSM-5®] criteria) 
<24 months prior to the Screening Visit.
13. The patient has any other disorder for which the treatment takes priority over treatment of 
cCH or is likely to interfere with study treatment or impair treatment compliance.
14. The patient has a history of moderate or severe head trauma or other neurological 
disorder or systemic medical disease that is, in the investigator’s opinion, likely to affect 
central nervous system functioning.
15. The patient has a history of cancer, other than basal cell or Stage 1 squamous cell 
carcinoma of the skin, that has not been in remission for >5 years prior to the first dose of 
eptinezumab. Male patients with abnormal prostate-specific antigen (PSA) levels 
according to national/local guideline may be enrolled in the study provided they have 
been followed up, have been asymptomatic and have had no treatment for prostate 
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cancer. Patients under surveillance for a low and stable level of M-component are 
allowed.
16. 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).
17. The patient has or has had one or more of the following conditions that is/are considered 
clinically relevant in the context of the study: other neurological, pulmonary, hepatic, 
endocrinological, gastrointestinal, haematological, infectious, immunological or ocular 
disorder.
18. The patient takes or has taken recent or concomitant medication that is disallowed or 
allowed with restrictions (specified in Appendix II) or it is anticipated that the patient will 
require treatment with at least one of these medications during the study.
19. The patient has one or more clinically significant out-of-range vital signs at the Screening 
Visit.
20. The patient has a BMI >39 kg/m2 at the Screening Visit.
21. The patient has been previously tested positive for human immunodeficiency virus 
(HIV), hepatitis B surface antigen (HBsAg) or Hepatitis C virus antibody (anti-HCV).
22. The patient has one or more clinical laboratory test values outside the reference range, 
based on the blood and urine samples taken at the Screening Visit, that are of potential 
risk to the patient’s safety, or the patient has, at the Screening Visit:
a serum creatinine value >1.5 times the upper limit of the reference range
a serum total bilirubin value >1.5 times the upper limit of the reference range
a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2 times the upper limit of the reference range.
23. The patient has, at the Screening Visit, an abnormal ECG that is, in the investigator’s 
opinion, clinically significant.
24. The patient is, at the Screening Visit or at the Baseline Visit, at significant risk of suicide 
(either in the opinion of the investigator or defined, using the C-SSRS, as the patient 
answering: "yes" to suicidal ideation questions 4 or 5 or answering: "yes" to suicidal 
behaviour within the past month). Patients who do not meet this criterion, but who are 
considered by the investigator to be at significant risk for suicide, are excluded.
25. The patient has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, or tolerability, or efficacy, or interfere with the 
conduct or interpretation of the study.
26. The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
27. The patient is hospitalised without consent or deprived of liberty due to a legal or 
administrative decision.
28. The patient s under legal guardianship and unable to provide his consent.
29. The patient is not covered by the national mandatory health insurance plan (when 
applicable according to the country-specific law).
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6
Investigational Medicinal Product
6.1
Treatment Regimen
Patients will receive four infusions with eptinezumab 400 mg at 12-week intervals at Day 0 
(Visit 2), at the end of Weeks 12 (Visit 5), 24 (Visit 8) and 36 (Visit 11), administered as an 
IV infusion over 45 minutes (+15 minutes).
6.2
Withdrawal Criteria
A patient must be withdrawn from the study if:
the patient withdraws his or her consent (defined as a patient who explicitly takes back his 
or her consent); section 8.7 states how the patient’s data will be handled;
the patient has been enrolled in error;†
the patient fails to comply with study procedures;
the patient is lost to follow-up (defined as a patient who fails to comply with scheduled 
study visits or contact, who has not actively withdrawn from the study, and for whom no 
alternative contact information is available [this implies that at least two documented 
attempts have been made to contact the patient]);
the 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.
A patient must be withdrawn from treatment if:
the investigator considers it, for safety, lack of efficacy, and/or study compliance reasons, 
in the best interests of the patient that he or she be withdrawn from treatment;
the patient becomes pregnant;
the patient has a serum ALT or AST value >3 times the upper limit of the reference range 
and a serum total bilirubin value >2 times the upper limit of the reference range;
the patient has a serum ALT or AST value >5 times the upper limit of the reference range 
that is confirmed by re-testing <2 weeks later;
the patient has a QTcF interval >500 ms; the decision to withdraw the patient may be 
postponed until a repeat ECG is taken, if ECG is taken within 24 hours;
the patient experiences an anaphylactic reaction or another serious and/or severe 
hypersensitivity reaction to the eptinezumab infusion, as assessed by the investigator. If the 
event occurs during the infusion, the infusion must be discontinued immediately.
Patients who withdraw will not be replaced.
†
If patient has been enrolled in error and has not been administered eptinezumab, the patient must be 
withdrawn. Withdrawal of patients enrolled in error and who have received eptinezumab should be 
based on a case-by-case evaluation of the individual risk/benefit. The decision about the 
administration of the second dose of eptinezumab will be based on an individual risk/benefit 
assessment as judged by the investigator.
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Patients who withdraw from the study, except for those who withdraw their consent, will be 
asked to attend a Withdrawal Visit as soon as possible and a further SFU Visit, scheduled 
20 weeks (5 half-lives) after the last eptinezumab administration.
Patients who are withdrawn from the treatment will be given the opportunity to remain in the 
study at the discretion of the investigator. Patients will be expected to attend all scheduled 
study visits and procedures except eptinezumab administration. If patients refuse, they will be 
asked to attend a Withdrawal Visit as soon as possible and a further SFU Visit, scheduled 
20 weeks (5 half-lives) after the last eptinezumab administration.
6.3
IMP, Formulation, and Strength
The IMP supplied by Lundbeck in this study is:
Eptinezumab 100 mg/mL (1mL/vial) as concentrate for solution for infusion.
400 mg eptinezumab will be dispensed as 4 vials of 100 mg/mL (1mL/ vial), concentrate for 
solution for infusion. 4 x 1 mL of 100 mg/mL concentrate for solution for infusion is added to 
100 mL of 0.9% normal saline, intravenously.
Doses will be administered intravenously over a period of 45 (+15) minutes by the 
investigator or designee.
If the infusion is not completed or temporarily interrupted, the reason for the interruption 
must be recorded in the electronic case report form (eCRF) and in the patient’s medical 
records. If the investigator stops or pauses the infusion due to a potential safety or tolerability 
issue, an Adverse Event should be recorded.
Further instructions on preparation and procedures associated with administering the IV can 
be found in the Pharmacy Manual and Infusion Guidelines.
6.4
Manufacturing, Packaging, Labelling, and Storage of IMP
The IMP will be manufactured, packaged, labelled, released (by a qualified person [QP]), and 
distributed in accordance with the principles of Good Manufacturing Practice, under the 
responsibility of Lundbeck.
The IMP will be provided in a patient kit containing 4 single-use vials (as a concentrate for 
solution for infusion).
The wording on the labels will be in accordance with Good Manufacturing Practice regarding 
labelling and national and/or local regulatory requirements. If additional information is to be 
added when the IMP is dispensed to the patients, this will be clearly stated on the labels, and 
the investigator will be instructed to do so.
No manipulation, repackaging, or relabelling of IMP is permitted after QP release by 
Lundbeck, unless a repackaging/relabelling agreement exists, and the documentation is 
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available to Clinical Supply, H. Lundbeck A/S, and, where necessary, new QP releases are 
made.
The IMP will be identified using a unique kit IMP number.
The IMP must be stored in a safe and secure location, and in accordance with the storage 
conditions specified on the label.
6.5
Method of Assigning Patients to Treatment
Interactive response technology (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. Assignment of IMP will be carried out in the IRT. Further information 
can be found in the Pharmacy Manual.
6.6
IMP Accountability
IMP accountability is documented in the IRT.
The investigator and the pharmacist must agree to only dispense IMP to patients enrolled in 
the study. The investigator or the pharmacist must maintain an adequate record of the receipt 
and distribution of the IMP. This record must be available for inspection at any time.
7
Concomitant Medication
Concomitant medication is any medication other than eptinezumab that is taken during the 
study from up to 3 months prior to the Screening Visit until the SFU Visit.
The concomitant medications that are disallowed or allowed with restrictions during the study 
are summarised in Appendix II.
Abortive therapy for cluster headache is allowed for the entire duration of the study (refer to 
list of therapies in Appendix II). Specific transitional and preventive treatments for cluster 
headache are allowed with restrictions (refer to list of therapies in Appendix II)
Details of all concomitant medication (prescription and over-the-counter) taken <3 months 
prior to the Screening Visit must be recorded in the eCRF at the first visit. Any changes 
(including reason for changes) in concomitant medication must be recorded at each 
subsequent visit.
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.
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Use of Coronavirus Disease 2019 Vaccine
There is currently no data indicating that eptinezumab may interact with or impair the body´s 
immunological response to the COVID-19 vaccines. Hence, there are no indications for safety 
concerns of concomitant use of the COVID-19 vaccines with eptinezumab. As such, 
COVID-19 vaccination is allowed during the eptinezumab studies with the guidance measures 
as described below.
If possible, a time window of at least 14 days should be allowed between COVID-19 
vaccination and the Screening Visit. If the patient has recently received a COVID-19 vaccine, 
the investigator should judge if the patient can be administered eptinezumab infusion at the 
scheduled visit based upon the patient’s individual response to the COVID-19 vaccine. As a 
precautionary measure, the COVID-19 vaccine should not be given within ±3 days of 
eptinezumab infusion.
In the current study, if a patient is administered a COVID-19 vaccine (or any other 
prophylactic vaccine or other concomitant medication), this should be captured as 
concomitant medication in the eCRF, including the date that the vaccine was given. The name 
of the manufacturer and, if applicable, whether it was the “first” or “last” vaccination should 
also be added, in a bracket for example.
All adverse events, including those judged by the investigator to be related to the COVID-19 
vaccine, must be captured in the eCRF on the Adverse Event Form. A causality assessment, 
including an alternative causality as relevant, must be provided on the Adverse Event Form.
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 section 9.
The study consists of a Screening Period (4 weeks), a Treatment Period (48 weeks), and a 
Safety Follow-up Period (8 weeks). After the Screening Period, the patient will attend the 
Baseline Visit (Day 0/Visit 2), which is the first visit of the Treatment Period. All patients 
will receive four IV infusions with eptinezumab 400 mg administered at 12-week intervals at 
Day 0 (Visit 2), at the end of Weeks 12 (Visit 5), 24 (Visit 8) and 36 (Visit 11). For all 
patients, who complete the study, a SFU Visit will be conducted 20 weeks (5 half-lives) after 
the last infusion of eptinezumab, that is at Week 56. For patients who withdraw from the 
study, the SFU Visit will be conducted 20 weeks (5 half-lives) after their last eptinezumab 
infusion.
The following visits will be site visits:
Screening Visit at Week -4 (Visit 1)
Baseline Visit at Week 0 (Day 0/Visit 2) – first eptinezumab infusion
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IMP Visits at Weeks 12, 24 and 36 (Visits 5, 8 and 11 - second, third, and fourth 
eptinezumab infusion)
Completion Visit at Week 48 (Visit 14)
SFU Visit at Week 56 (Visit 15)
Withdrawal Visit (if applicable) - Patients who withdraw, except for those who withdraw 
their consent, will be asked to attend a Withdrawal Visit as soon as possible and a further 
SFU Visit, scheduled 20 weeks (5 half-lives) after the last eptinezumab administration.
All other study visits will be phone contact visits.
Patients will be given an eDiary at the Screening Visit (Visit 1, Week -4) and must be trained 
by the clinical site staff in its use and compliance requirements. Patients will complete eDiary 
entries daily during the Screening Period (from Week -4 to Day 0) and during the first 4 
weeks that follow each eptinezumab infusion (Weeks 1 to 4, 13 to 16, 25 to 28, and 37 to 40), 
and weekly for Weeks 5 to 12, 17 to 24, 29 to 36, and 41 to 48. Patients must complete the 
daily eDiary and ePRO entries prior to infusion and prior to any interaction with the clinical 
site staff. At each clinic visit and phone contact, a compliance check of the eDiary data will be 
conducted by the clinical site staff. In addition to the eDiary compliance checks performed at 
the defined study visits, ongoing evaluation of eDiary compliance will be performed by the 
clinical site (based on eDiary reporting) and more frequent contact with patients may be 
performed in case of non-compliance.
If the date of a clinic visit or phone contact does not conform to the schedule, subsequent 
visits should be planned to maintain the visit schedule relative to the Baseline Visit 
(Day 0/Visit 2).
In exceptional situations to be approved by the CRO’s medical monitor, site visits may only 
consist of blood and urine sampling (for clinical safety laboratory tests, exploratory
eptinezumab quantification, ADA including NAb, and exploratory biomarkers), ECG, vital 
signs, physical and neurological examinations, adverse events recording, and eptinezumab 
administration, while the remaining assessments (eDiary, ePROs, C-SSRS, and investigator 
evaluations) can be conducted remotely as virtual clinic visits in line with the US FDA and 
EMA guidances.36, 37
During the Treatment Period, ePROs which are scheduled in alignment with a clinic visit can
be completed in the clinic or in the remote setting within 3 days prior to the scheduled visit 
date. ePROs which are scheduled in alignment with a phone contact must be completed in the 
remote setting and can be completed on the day or within 3 days prior to the scheduled phone 
contact date.
After completing or withdrawing from the study, the patient must be treated in accordance 
with usual clinical practice.
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8.2
Screening Visit (Visit 1)
Signed informed consent must be in place before any study-related assessments are performed 
and may be obtained at the Screening Visit.
At the Screening Visit, the patient will be asked to sign the main Informed Consent Form and 
the Informed Consent Form for blood sampling for pharmacogenetics (optional). Depending 
of the country requirements, the number of ICFs may be different. Under exceptional 
circumstances, the discussion with the patients about the Informed Consent Form(s) can be 
done as a virtual clinic visit and the Informed Consent Form(s) can be provided remotely in 
line with the US FDA and EMA guidances.36, 37 According to EMA guidance, this could 
comprise contacting the patients via phone or video-calls and obtaining oral consents, to be 
documented in the patients' medical records, supplemented with email confirmation. Any 
consent obtained this way should be documented and confirmed by way of normal consent 
procedures at the earliest opportunity when the patients are back at the clinical sites.37
After the Screening Visit, a review of the data is required by the CRO medical monitor prior 
to the Baseline Visit (Day 0/Visit 2), to advise if the patient appears eligible and 
recommended to continue with the study procedures.
Re-screening for the Screening Visit is allowed according to criteria outlined in section 8.2.3.
For women of childbearing potential, a pregnancy test must be performed at the Screening 
Visit using serum beta-human chorionic gonadotropin (β-hCG). The investigator must check 
and document current contraceptive methods. If relevant to do so, contraceptive therapy 
should be initiated if agreed by the patient and if there are no contraindications for the 
initiation of contraception.
At the Screening Visit, the patient will be assisted with the provisioning and training of the 
eDiary and ePROs by the clinical site staff. Details will be provided in a separate user manual. 
See section 9.2.1.2 for further details on eDiary.
The Screening Visit assessments may be extended over several days if needed. The date of the 
first assessment (except Informed Consent Form) should be entered in eCRF as the visit date.
In this case, eDiary must be provided to the patient on the date of that first assessment, which 
is considered as the first day of the 28-day Screening Period.
8.2.1
Pre-Screening
Each site must record in a pre-screening log which patients attended the Screening Visit.
8.2.2
Patient Identification Card
Each patient will be provided with a patient identification card that states, at a minimum, the 
name of the IMP, the study number, the patient identification number, the investigator’s 
name, and an emergency telephone number providing 24-hour service.
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The patient identification card should be returned to the investigator upon completion of the 
patient’s participation in the study.
8.2.3
Re-Screening Visit
The Re-Screening Visit must be conducted as a visit to the clinical site. Re-screening is only 
allowed for patients with a complete Screening Visit and who fail to meet one or more of the 
following selection criteria:
1. If the diagnosis of cCH as defined by IHS ICHD-3 classification4 cannot be confirmed 
due to disease duration of less than 12 months during the maximum duration of the 
Screening Period, including the potential 1-week extension of this period granted by 
the CRO’s medical monitor (Inclusion criterion N°8).
2. If the patient does not have during the Screening Period, based on prospectively-collected 
information in the eDiary, a cluster headache attack frequency of minimum 14 cluster 
headache attacks for the 28-day Screening Period (Inclusion criterion N°10).
3. If the patient has demonstrated poor compliance with the eDiary during the maximum 
duration of the Screening Period, including the potential 1-week extension of this 
period granted by the CRO’s medical monitor, due to well documented reasons 
(sickness, travels, technical eDiary issues, or others) (Inclusion criterion N°11).
4. If the patient does not fulfil Exclusion criterion N°3 (previous participation in a clinical 
study <30 days or has taken any investigational products within 5 plasma half-lives 
(whichever is longer) prior to the Screening Visit.
5. If the patient does not fulfil Exclusion criterion N°18 (Disallowed medications or 
medications allowed with restrictions), refer to Appendix II:
The required duration of a washout period for a medication that is disallowed prior to 
screening, or,
A stable usage period for a medication that is allowed with restrictions prior to 
screening.
The patient must already have either started the washout prior to screening or be on the 
allowed dosage as part of their standard clinical care. Washout or change in dosage may 
not be done specifically for inclusion into this study, but only if clinically indicated.
6.
Patients with uncontrolled high blood pressure at the Screening Visit (Exclusion criteria 
N°16 and 19): may be considered for re-screen once their blood pressure is controlled in 
the opinion of the investigator; any use of antihypertensive medication and dose must be 
stable for at least 2 months prior to the Re-Screening Visit.
7.
Patients with a BMI ≥39 kg/m2 (Exclusion criterion N°20).
8.
A patient has answered "yes" to suicidal ideation questions 4 or 5 of the C-SSRS or "yes" 
to suicidal behaviour within the past month (Exclusion criterion N°24). These screen-fail 
patients may be considered for re-screen if the following conditions are met:
The patient was referred to an appropriate mental health professional and received 
treatment.
At least 6 months has elapsed since the screen-fail.
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The patient has not answered "yes" to suicidal ideation questions 4 or 5 of the C-SSRS 
or "yes" to suicidal behaviour within the past 6 month, and are not considered by the 
investigator to be at significant risk for suicide.
9.
For patients affected by COVID-19 during the Screening Period, that is being in 
quarantine with a positive COVID-19 test with or without symptoms or other reasons 
related to COVID-19 which impacts the patients study participation, there will be an 
option of re-screening upon approval from the CRO’s medical monitor.
At the new Screening Visit, the patient must sign new Informed Consent Form(s). At the new 
Screening Visit, the patient will be assigned a new screening number. A re-screened patient 
must have a complete new Screening Visit, and all the eligibility criteria must be re-assessed 
at the new Screening Visit.
The decision and the planning for re-screening must be based on a discussion between 
patients and investigators. Due to the short enrolment period, re-screening will only be 
possible if the study is still enrolling patients. Authorisation for re-screening may only be 
granted by the CRO’s medical monitor after a thorough review of all data from the original 
Screening Visit.
The following information will also be recorded in the eCRF at the new Screening Visit:
that the patient has previously been screened for the study;
that re-screening has been authorised by the CRO’s medical monitor;
the screening number that was assigned to the patient at the original Screening Visit.
If a patient is re-screened, no data from the original Screening Visit will be used.
A patient may only be re-screened once.
8.2.4
Extension of Screening Period
Extension of the Screening Period is only allowed for patients with a complete Screening 
Visit and who fail to meet one or more of the following selection criteria:
1.
If the patient does not have during the Screening Period, based on prospectively collected 
information in the eDiary, a cluster headache attack frequency of minimum 14 cluster 
headache attacks for the 28-day Screening Period (Inclusion criterion N°10).
2.
If the patient has demonstrated poor compliance with the eDiary during the 4-week 
Screening Period due to well documented reasons (sickness, travels, technical eDiary 
issues, or others) (Inclusion criterion N°11).
3.
If the patient does not fulfil Exclusion criterion N°18 (Disallowed medications or 
medications allowed with restrictions, refer to Appendix II) and the investigator considers 
that the criterion can be met by allowing additional 7 days in the Screening period.
In these cases, the Screening Period may be extended for a maximum of 7 additional days, 
and the eligibility of patients will be assessed on the last 28 days before baseline.
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Request for extension of the Screening Period must be immediately notified and discussed 
with the CRO’s medical monitor after a thorough review of all data from the original 
Screening Visit.
8.3
Baseline Visit (Day 0/Visit 2) + IMP infusion
The Baseline Visit (Day 0/Visit 2) also includes eptinezumab administration and will occur 4 
weeks after the Screening Visit. Inclusion and exclusion criteria review must be done prior to
dosing at the Baseline Visit (Day 0/Visit 2).
A blood sample for pharmacogenetics (optional) shall be taken prior to eptinezumab infusion.
For procedures preceding and following eptinezumab administration, see section 8.4.
8.4
IMP Visits (Visits 2, 5, 8 and 11) + IMP infusion
At IMP Visits, the patients will receive an eptinezumab infusion. See section 6.1 and Infusion 
Guidelines for further instructions on procedures associated with administering IV 
eptinezumab.
eDiary and ePRO must be completed prior to infusion and prior to any interaction with the 
clinical site staff. During the Treatment Period, ePROs which are scheduled in alignment with 
a clinic visit can be completed in the clinic or in the remote setting within 3 days prior to the 
scheduled clinic visit date.
A compliance check of eDiary data will be conducted by the clinical site staff and the patient 
will be assisted with re-training if necessary. In addition to the eDiary compliance checks 
performed at the defined study visits, ongoing evaluation of eDiary compliance will be 
performed by the clinical site (based on eDiary reporting) and more frequent contact with the 
patients may be needed in case of non-compliance. See section 9.2.1.2 for further details on 
eDiary.
Prior to eptinezumab infusion:
Patients must complete the eDiary and ePROs. ePROs must be completed prior to blood 
and urine sampling.
Vital signs must be assessed prior to blood sampling.
The following assessments must be conducted: vital signs (including body temperature), 
weight, concomitant medications, adverse events, ECG, blood sampling (for clinical safety 
laboratory tests, exploratory eptinezumab quantification, ADA including NAb, and 
exploratory biomarkers), urine sampling (for clinical safety laboratory and pregnancy 
tests), physical and neurological examinations (if done at the discretion of the investigator), 
and C-SSRS administration.
C-SSRS will be administered by the authorised rater at the clinic.
During eptinezumab infusion: Patients must be monitored for adverse events.
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After end-of-eptinezumab-infusion, before the patient is discharged from the clinical site:
Patients must be monitored for at least 1 hour.
The following assessments must be conducted: vital signs (including body temperature), 
and the patient must be monitored for adverse events. Vital signs must be assessed prior to 
blood sampling.
A blood sample for exploratory eptinezumab quantification and exploratory biomarkers 
must be taken within approximately 1 hour after end of infusion.
Blood samples for biobanking (gene expression profiling, and metabolomics/proteomics) 
shall be drawn prior to the first and the third eptinezumab infusion at Visits 2 and 8.
Patients will be requested to stay longer should the investigator or designee determine this is 
clinically warranted. After the infusion, the patients will be under observation, but not 
confined to bed, unless the investigator decides, based on the patient’s condition, that it is in 
the best interest of the patient to be confined to bed.
8.5
Phone Contacts (Visits 3, 4, 6, 7, 9, 10, 12, 13)
The patient will be contacted via phone for eDiary compliance checks to ensure that selected 
ePROs assessments have been completed and for collection of relevant information such as 
adverse events and concomitant medication.
A compliance check of eDiary data will be conducted by the clinical site staff and the patient 
will be assisted with re-training if necessary. In addition to the eDiary compliance checks 
performed at the defined study visits, ongoing evaluation of eDiary compliance will be 
performed by the clinical site (based on eDiary reporting) and more frequent contact with 
patients may be needed in the case of non-compliance. See section 9.2.1.2 for further details 
on eDiary.
Additionally, the following ePROs must be completed in the remote setting in alignment with 
the scheduled phone contacts (see Panel 2): PGIC (Visits 3, 4, 6, 7, 9, 10, 12, 13), and SIS, 
EQ-5D-5L, HCRU, and WPAI:GH2.0 (Visits 3, 6, 9, 12). During the Treatment Period, 
ePROs which are scheduled in alignment with a phone contact must be completed in the 
remote setting and can be completed on the day or within 3 days prior to the scheduled phone 
contact date.
Only the clinical site staff trained and listed in the delegation log will conduct phone contacts 
and hence be allowed to call the patient. Each phone contact must be documented in medical 
notes and used for source data verification when completing the eCRF and for subsequent 
monitoring.
Phone contacts should be planned to maintain the visit schedule relative to the Baseline Visit 
(Day 0/Visit 2).
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8.6
Completion Visit (Visit 14)
At the Completion Visit, the patient must be assisted with the closeout of the eDiary.
Blood samples for biobanking (gene expression profiling, and metabolomics/proteomics) 
shall be drawn at the Completion Visit.
8.7
Withdrawal Visit
Three different scenarios can occur, depending on whether the patients withdraw from the 
study, from treatment or withdraw their consent.
Patients who withdraw from the study prior to the Completion Visit (Week 48/Visit 14), 
except for those who withdraw their consent, will be asked to attend a Withdrawal Visit as 
soon as possible and a further SFU Visit, scheduled 20 weeks (5 half-lives) after the last 
eptinezumab administration.
Patients who are withdrawn from the treatment prior to the Completion Visit (Week 48/Visit 
14) will be given the opportunity to remain in the study at the discretion of the investigator. 
Patients will be expected to attend all scheduled study visits and procedures except 
eptinezumab administration. If patients refuse, they will be asked to attend a Withdrawal Visit 
as soon as possible and a further SFU Visit, scheduled 20 weeks (5 half-lives) after the last 
eptinezumab administration.
No new information will be collected from patients who withdraw from the study or decide to 
withdraw, except information collected in relation to the scheduled Withdrawal Visit and SFU 
Visit or needed for the follow-up of adverse events (section 10.5).
The reason for withdrawal must be recorded in the eCRF, and the investigator must ask 
specifically whether withdrawal was due to an adverse event.
For a patient who withdraws consent:
if the patient withdraws consent during a site visit and then agrees to it being the final visit, 
the investigator will complete the visit as a Withdrawal Visit and all the data collected up 
to and including that visit will be used;
if the patient withdraws consent during a telephone conversation, the investigator will ask 
the patient if he or she will attend a Withdrawal Visit. If the patient:
agrees to attend a Withdrawal Visit, all the data collected up to and including that visit 
will be used;
refuses to attend a Withdrawal Visit, the investigator should attempt to follow the 
patient’s safety and future treatment; any information collected will only be recorded in 
the patient’s medical records;
if the patient explicitly requests that the patient’s data collected from the time of 
withdrawal of consent onwards not be used, this will be respected.
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8.8
Safety Follow-up Visit (Visit 15)
The SFU Visit must be conducted as a visit to the clinical site. The SFU Visit should be 
conducted 20 weeks (5 half-lives) after the last eptinezumab administration.
The SFU Visit will be conducted to capture adverse events that occur after the 
Completion/Withdrawal Visit, as well as to follow up on the outcome of adverse events 
ongoing at the Completion/Withdrawal Visit.
Patients who withdraw from the study, except for those who withdraw their consent, will be 
asked to attend a Withdrawal Visit as soon as possible after withdrawal, and a further SFU 
Visit, scheduled 20 weeks (5 half-lives) after the last eptinezumab administration.
For adverse events that were ongoing at the Completion/Withdrawal Visit and that resolved 
during the SFU Period, the stop date must be recorded. For non-serious adverse events still 
ongoing at the safety follow-up, the Ongoing Adverse Event checkbox on the Adverse Event 
Form must be ticked. Serious adverse events (SAEs) must be followed until resolution or the 
outcome is known.
The safety follow-up for patients who withdraw consent must be performed, if at all possible; 
any information collected will be recorded in the patients’ medical records.
8.9
Unscheduled Visit
Unscheduled visits can be completed if required as either site visit or telephone visits. At
these visits, clinical safety laboratory tests, ECG, vital signs, physical examination,
neurological examination, C-SSRS, body measurement, mental health consultation
information or pregnancy tests can be performed. In case of any additional tests performed not 
covered by the existing tests specified in the protocol and the eCRF, the results can be 
reported in connection with an AE reporting (see section 10) or documented in the medical 
records, as applicable.
8.10
End-of-study Definition
The end of the study for an individual patient is defined as the last protocol-specified contact 
with that patient. The overall end of the study is defined as the last protocol-specified contact 
with the last patient ongoing in the study.
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9
Assessments
9.1
Screening and Baseline Procedures and Assessments
9.1.1
Demographics and Baseline Characteristics
Prior to enrolling a patient in the study, the investigator must ascertain that the patient meets 
the selection criteria. Refer to section 5.3.
The following assessments will be performed after the Informed Consent Form(s) have been 
signed at the Screening Visit (Week -4/Visit 1):
Demographics (age, sex, race). Race will not be collected if restricted per local regulations
Prior cCH documented history for review and documentation of previous treatment for 
cCH within 12 months prior to the Screening Visit (see section 12 for definition of 
adequately documented records)
Other recent medication (past 3 months)
Relevant history (social, medical, psychiatric, neurological)
Substance use (e.g., smoking and alcohol consumption)
Height
Family history of cluster headache
Urine drug screen
Adverse events (serious and non-serious) present at Screening Visit must be collected, 
recorded, and reported to Lundbeck from the time the patient has signed the Informed 
Consent Form(s) at the Screening Visit
Serum pregnancy test and collection of contraception measures (for women of childbearing
potential)
Blood and urine samples for clinical safety laboratory tests
Vital signs (including body temperature), weight
ECG
Examinations (physical, neurological)
C-SSRS
eDiary/ePRO training
eDiary recording
The following assessments will be performed at the Baseline Visit (before eptinezumab
administration):
Inclusion/exclusion criteria
eDiary recording and ePROs
Adverse events (serious and non-serious) must be collected, recorded, and reported to 
Lundbeck from the time the patient has signed the Informed Consent Form(s) at the 
Screening Visit
Concomitant medication
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Urine pregnancy test (for women of childbearing potential)
Blood and urine samples for clinical safety laboratory tests
Blood samples for exploratory eptinezumab quantification, exploratory biomarkers, ADA 
including NAbs, and biobanking
Blood samples for pharmacogenetics (optional)
Vital signs (including body temperature), weight
ECG
Examinations (physical, neurological) at the discretion of the investigator
C-SSRS
eDiary compliance check
9.1.2
Diagnostic Assessments
IHS ICHD-3 guidelines4 sections 3.1 and 3.1.2 for cCH are the diagnostic criteria to be used 
when assessing patient eligibility. Fulfilment of criteria for cCH according to the inclusion 
criteria in this protocol will be confirmed via prospectively-collected information in the 
eDiary during Screening Period, that is CH attack frequency of minimum 14 attacks during
the 28-day Screening Period. The lower limit for CH attack frequency is in line with the 
IHS ICHD-3 criteria for CH. 
Definition of an eDiary Compliant Day: A Compliant Day is defined as any day where:
a headache event is reported 
or evening diary is completed confirming patient did not have any new headache to report
Prior to enrolment, the investigator will review the data in the eDiary Eligibility Report to 
determine if eligibility criteria are fulfilled.
Panel 4
IHS ICHD-3 Guidelines for Chronic Cluster Headache
3.1 Cluster Headache
A.
At least five attacks fulfilling criteria B–D
B.
Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15–180 minutes (when 
untreated)
C.
Either or both of the following:
(1) at least one of the following symptoms or signs, ipsilateral to the headache:
a.
conjunctival injection and/or lacrimation
b.
nasal congestion and/or rhinorrhoea
c.
eyelid oedema
d.
forehead and facial sweating
e.
miosis and/or ptosis
(2) a sense of restlessness or agitation
D.
Occurring with a frequency between one every other day and eight per day
E.
Not better accounted for by another ICHD-3 diagnosis.
3.1.2 Chronic cluster headache
A.
Attacks fulfilling criteria for 3.1 Cluster headache and criterion B below
B.
Occurring without a remission period, or with remissions lasting <3 months, for at least 1 year.
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Chronic cluster headache may arise de novo (referred to as primary cCH) or evolve from 
episodic cluster headache (secondary cCH). In some patients change occurs from cCH to 
episodic cluster headache.4
9.1.3
Drug Screen
A urine drug screen will be performed at the central laboratory for the Screening Visit only. A 
positive result must be discussed with the CRO’s medical monitor.
9.2
Efficacy Assessments
Efficacy assessments include the eDiary to record daily/weekly cluster headache data and 
ePROs (PGIC, SIS).
Patients will record cluster headache data on an eDiary from the Screening Period (Visit 1, 
Week -4) until the Completion Visit (Week 48/Visit 14):
On a daily basis during the Screening Period (from Week -4 to Day 0) and during the first 
4 weeks that follow each eptinezumab infusion (Weeks 1 to 4, 13 to 16, 25 to 28, and 37 to 
40);
On a weekly basis for Weeks 5 to 12, 17 to 24, 29 to 36, and 41 to 48.
Patients will complete the PGIC and SIS along with the pharmacoeconomic assessment 
ePROs (see section 9.3). It is preferable that the scheduled time of the day for the assessments 
is as consistent as possible across all the study visits.
ePROs will be completed in alignment with clinic visits and phone contacts (see Panel 2):
ePROs which are scheduled in alignment with a clinic visit:
can be completed in the clinic or in the remote setting within 3 days prior to the 
scheduled clinic visit date. On the day of IMP Visits (Day 0/Visit 2, Week 12/Visit 5, 
Week 24/Visit 8, and Week 36/Visit 11), patients must complete the ePROs prior to 
infusion and prior to any interaction with the clinical site staff.
ePROs which are scheduled in alignment with a phone contact:
must be completed in the remote setting and can be completed on the day or within 
3 days prior to the scheduled phone contact date.
9.2.1
Clinical Outcome Assessments
9.2.1.1
Use of Clinical Outcome Assessments Tools
The clinical outcome assessments (COA) tools are the eDiary and ePROs, guidance to 
patients on how to complete the tools will be given by designated clinical site staff (see 
section 9.2.1.6). Detailed instructions will be provided in a separate eDiary and ePRO 
Training Module.
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The COA tools will be administered in the local language. Only those provided by Lundbeck 
that have been validated in the language to which they have been translated will be used in 
this study.
The following COA tools will be used for efficacy assessments:
eDiary - to assess the number of daily/weekly cluster headache attacks, pain severity and 
medication use (that is the start and stop dates of cluster headache attacks and use of 
abortive cCH medications).
PGIC - to assess overall change in the severity of illness following treatment.
SIS - to assess quality of life resulting from insomnia as caused by cluster headache
attacks.
9.2.1.2
eDiary
At the Screening Visit (or at the date of the first assessment if assessments are extended over 
several days), the patient will be assisted with the provisioning of the eDiary and will be 
trained in eDiary use and compliance requirements by designated clinical site staff. Patients 
will be instructed to complete the eDiary on a daily basis, during the Screening Period (from 
Week -4 to Day 0) and during the first 4 weeks that follow each eptinezumab infusion (Weeks 
1 to 4, 13 to 16, 25 to 28, and 37 to 40), and on a weekly basis for Weeks 5 to 12, 17 to 24, 29 
to 36, and 41 to 48. The eDiary closeout must be performed while the patient is on site.
Details will be provided in a separate eDiary Training Module.
The content of the cluster headache diary is developed on key characteristics as mentioned in 
the definition of cCH (see section 9.1.2). The eDiary consists of applications and reports 
which will be used to derive the cluster headache endpoints and abortive medication use. The 
patient should record for each day/week if they experienced any cluster headache attacks. For 
each experienced cluster headache attack, the start date and time will be collected. The patient 
will record further daily/weekly information regarding the severity of pain associated to 
cluster headache and intake of cluster headache abortive medication. Cluster headache items 
will be assessed with a yes/no response; and severity of pain will be rated on an ordinal scale 
ranging from 0 to 4 (headache pain ratings: 0=none/barely any pain; 1=mild; 2=moderate; 
3=severe; 4=excruciating).48 Additional details regarding the questions that patients will 
answer can be found in the eDiary Training Module.
The Screening Visit will correspond to the day of eDiary distribution and will start the 28-day 
eDiary Screening Period. Any patient found to be ineligible for the study during Screening 
Period will not be enrolled. An eDiary Eligibility Report will be used to review baseline 
cluster headache attack days and eDiary compliance during the Screening Period for the 
eligibility assessment of:
a minimum 14 cluster headache attacks for the first 28 days of Screening Period
compliance by entry of cluster headache data for at least 24 out of the first 28 days of 
Screening Period.
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On the Baseline Visit (Day 0/Visit 2), patients must ensure to complete eDiary recording of 
cluster headache attacks that ended prior to infusion (that is for cluster headache attacks 
which are ongoing or not yet recorded in the eDiary).
On each day during the first 4 weeks that follow each eptinezumab infusion, the patient will 
be asked to record eDiary data for the day. On Weeks 5 to 12, 17 to 24, 29 to 36, and 41 to 48, 
and until the Completion Visit (Week 48/Visit 14)/Withdrawal Visit, the patient will be asked 
to record eDiary data for the week.
Clinical study site staff will be given access to the eDiary data. Compliance data (based on 
eDiary reporting) will be made available throughout the study to the clinical site staff for 
review on a regular basis. At least 24 out of the first 28 days compliance is needed during the 
Screening Period. At each clinic visit and phone contact, a compliance check of eDiary will 
be conducted by the clinical site staff. Additionally, ongoing evaluation of eDiary compliance 
will be performed by the clinical site and more frequent contact with patients may be needed 
in case of non-compliance. All follow-up with patients regarding eDiary compliance should 
be documented in the source records.
9.2.1.3
Patient Global Impression of Change
The PGIC is a single patient-reported item reflecting the patient’s impression of change in 
their disease status since the Baseline Visit (Day 0/Visit 2) (that is, in relation to activity 
limitations, symptoms, emotions, and overall quality of life). The item is rated on a 7-point 
scale, where a high score indicate improvement (very much improved; much improved; 
minimally improved; no change; minimally worse; much worse; very much worse). It takes 
approximate 1 minute to complete the scale.
9.2.1.4
Sleep Impact Scale
The SIS49 is a patient-reported scale to assess quality of life resulting from sleep disturbance. 
The SIS questionnaire includes 35 items belonging to 7 domains to assess sleep impact on: 
daily activities (5 items); emotional well-being (4 items); emotional impact (4 items); 
energy/fatigue (5 items); social well-being (6 items); mental fatigue (3 items); and satisfaction 
with sleep (8 items). Each item, for 6 out of the 7 domains, is rated on a 5-point scale ranging 
from 1 (“always” or “all of the time”) to 5 (“never” or “none of the time”), whereas 
satisfaction with sleep is rated on a 5-point scale ranging from 1 (very satisfied) to 5 (very 
dissatisfied). Each domain yields a score ranging from 0 to 100; items within each domain are 
summed and transformed using a formula. A higher score indicates better quality of life 
(reverse scoring for the satisfaction with sleep domain). It takes approximately 10 minutes to 
complete the SIS.
9.2.1.5
External Clinical Outcome Assessments Monitoring Oversight
Lundbeck reserves the right to use external quality oversight to ensure eDiary compliance and 
data quality, as well as ensure accurate completion of COAs. For this study, the CRO will 
conduct the external data monitoring (to be agreed with Lundbeck).
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9.2.1.6
Clinical Outcome Assessments Tool Training
The COA tools are patient-reported. Therefore, designated clinical site staff will receive 
guidance on good standards in completion of the COAs, in order to adequately train patients 
on completion of the eDiary and ePROs.
COA training will be conducted by the CRO (as agreed with Lundbeck). Clinical site staff 
will complete their designated training curriculum based on their initial qualification status 
and assigned role. Any exceptions must be discussed and approved by Lundbeck and/or its 
designee. The training program will also include general COA quality assurance and 
management guidance.
Only clinical site staff who have adequate experience with cluster headache and who have 
received adequate training on good standards in completion of the eDiary and ePROs will be 
authorised to train the patients on completion of the eDiary and ePROs in the study.
Documentation of training will be provided to the clinical site staff for archiving in the 
investigator site file and in the sponsor trial master file (TMF).
New eDiary and ePRO trainers joining the study must be trained similarly.
9.3
Pharmacoeconomic Assessments
Pharmacoeconomic assessments include ePROs (EQ-5D-5L, HCRU, WPAI:GH2.0).
Patients will complete these ePROs along with the efficacy assessment ePROs (PGIC and 
SIS, see sections 9.2.1.3 and 9.2.1.4). It is preferable that the scheduled time of the day for the 
assessments is as consistent as possible across all the study visits.
ePROs will be completed in alignment with clinic visits and phone contacts (see Panel 2):
ePROs which are scheduled in alignment with a clinic visit:
can be completed in the clinic or in the remote setting within 3 days prior to the 
scheduled clinic visit date. On the day of IMP Visits (Day 0/Visit 2, Week 12/Visit 5, 
Week 24/Visit 8, and Week 36/Visit 11), patients must complete the ePROs prior to 
infusion and prior to any interaction with the clinical site staff.
ePROs which are scheduled in alignment with a phone contact:
must be completed in the remote setting and can be completed on the day or within 
3 days prior to the scheduled phone contact date.
9.3.1
Clinical Outcome Assessments
9.3.1.1
Use of Clinical Outcome Assessments Tools
Refer to section 9.2.1.1 for further information on use of COA tools.
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The following COA tools will be used for pharmacoeconomic assessments:
EQ-5D-5L - to assess the overall state of health;
HCRU - to assess cluster headache-specific healthcare resource utilization;
WPAI:GH2.0 - to assess overall effect of health on productivity at work and daily 
activities.
9.3.1.2
EuroQol 5 Dimension – 5 Levels
The EQ-5D-5L50 is a patient-reported assessment designed to measure the patient’s 
well-being. It consists of 5 descriptive items (mobility, self-care, usual activities, 
pain/discomfort, and depression/anxiety) and a VAS of the overall health state. Each 
descriptive item is rated on a 5-point index ranging from 1 (no problems) to 5 (extreme 
problems) and a single summary index (from 0 to 1) can be calculated. The VAS ranges from 
0 (worst imaginable health state) to 100 (best imaginable health state). It takes approximately 
5 minutes to complete the EQ-5D-5L.
9.3.1.3
Health Care Resource Utilization
Cluster headache-specific healthcare resource utilization information will be collected in 
terms of outpatient health care professional visits, emergency room visits, hospital 
admissions, as well as duration of hospital stays during the past 4 weeks. Clinical site 
personnel and patients will be instructed to capture utilization that takes place outside of visits 
associated with their participation in the clinical study.
9.3.1.4
Work Productivity and Activity Impairment: General Health Second Version
The WPAI:GH2.051 is a patient self-rated scale designed to provide a quantitative measure of 
the work productivity and activity impairment due to a health condition. The WPAI:GH2.0 
assess activities over the preceding 7 days and consists of 6 items: 1 item assess employment 
(yes/no); 3 items assess the number of hours worked, the number of hours missed from work 
due to the patient’s condition, or due to other reasons; and 2 visual numerical scales to assess 
how much the patient’s condition affects their productivity at work and their ability to 
complete normal daily activities. It takes approximately 5 minutes to complete the 
WPAI:GH2.0.
9.3.1.5
External Clinical Outcome Assessments Monitoring Oversight
Lundbeck reserves the right to use external quality oversight to ensure eDiary compliance and 
data quality, as well as ensure accurate completion of COAs. For this study, the CRO will 
conduct the external data monitoring (to be agreed with Lundbeck).
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9.3.1.6
Clinical Outcome Assessments Training
The COA tools are patient-reported. Therefore, designated clinical site staff will receive 
guidance on good standards in completion of the COAs, in order to adequately train patients 
on completion of the eDiary and ePROs.
COA training will be conducted by the CRO (as agreed with Lundbeck). Clinical site staff 
will complete their designated training curriculum based on their initial qualification status 
and assigned role. Any exceptions must be discussed and approved by Lundbeck and/or its 
designee. The training program will also include general COA quality assurance and 
management guidance.
Only clinical site staff who have adequate experience with cluster headache and who have 
received adequate training on good standards in completion of the eDiary and ePROs will be 
authorised to train the patients on completion of the eDiary and ePROs in the study.
Documentation of training will be provided to the clinical site staff for archiving in the 
investigator site file and in the sponsor TMF.
New eDiary and ePRO trainers joining the study must be trained similarly.
9.4
Pharmacokinetic Assessments (Blood Sampling for Exploratory Eptinezumab 
Quantification)
The blood samples (maximum total volume: 10.5 mL per patient) for exploratory 
eptinezumab quantification in plasma will be drawn in accordance with Panel 2. The blood 
sampling and handling procedures are described in the study-specific Laboratory 
Specification Manual.
The bioanalysis will be performed by a contracted laboratory under the responsibility of 
Bioanalysis - Biologics, H. Lundbeck A/S, according to a protocol approved by Lundbeck.
The results will be subjected to a pharmacokinetic analysis, that will be reported separately.
9.5
Pharmacodynamic Assessments (Exploratory Biomarkers)
Blood samples (maximum total volume 36 mL) for the pharmacodynamic/exploratory 
biomarkers including assessment of the CGRP and eptinezumab-CGRP complex will be 
collected in accordance with Panel 2. The blood sampling and handling procedures are 
described in the study-specific Laboratory Specification Manual.
The results from these analyses will be reported separately.
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9.6
Safety Assessments
9.6.1
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 when the 
patient signs the Informed Consent Form(s). 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 eptinezumab. 
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.
At IMP Visits, adverse events are monitored prior to, during, and after infusion.
See section 10 for further information on adverse events.
9.6.2
Clinical Safety Laboratory Tests
The clinical safety laboratory tests are listed in Panel 5.
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Panel 5
Clinical Safety Laboratory Tests
Haematology
Liverb
Infectionc
B-haemoglobin [HGB]
B-erythrocyte count [RBC]
B-total leucocyte count [WBC]
B-neutrophilsa [NEUTLE]
B-eosinophilsa [EOSLE]
B-basophilsa [BASOLE]
B-lymphocytesa [LYMLE]
B-monocytesa [MONOLE]
B-thrombocyte count [PLAT]
B-haematocrit [HCT]
P-prothrombin time [PT]
S-total bilirubin [BILI]
S-conjugated bilirubin [BILDIR]
S-alkaline phosphatase [ALP]
S-alanine aminotransferase [ALT]
S-aspartate aminotransferase [AST]
S-gamma-glutamyl transferase [GGT]
S-C-reactive protein [CRP]
Immune response lab kite
P-histamine [HISTAMINE]
S-tryptase [TRYPTASE]
immunoglobulin E [IgE]
complement C3, C4 [C3 and 
C4]
Electrolytesb
Kidneyb
Urinef
S-sodium [SODIUM]
S-potassium [K]
S-calcium (total) [CA]
S-creatinine [CREAT]
S-urea nitrogen [UREAN]
U-protein (dipstick) [PROT]
U-glucose (dipstick) [GLUC]
U-blood (dipstick) [OCCBLD]
Urine drug screenc
Endocrine and Metabolicb
Lipidsb,d
Pregnancyg
S-albumin [ALB]
S-glucosed [GLUC]
B-HbA1c [HBA1C]
S-creatine phosphokinase [CK]
S-low density lipoprotein [LDL]
S-high density lipoprotein [HDL]
S-triglycerides [TRIG]
S-cholesterol (total) [CHOL]
S-hCGh [HCG]
Urine (dipstick)
B = blood; P = plasma; S = serum; U = urine
a
Count and % of total leucocytes
b
Clinical chemistry
c
Performed at the Screening Visit only
d
Fasting, when possible
e
Performed per investigator judgement, see section 10.1.3.
f
If urine dipstick is positive, a urine microscopic panel will be conducted
g
Only for women of childbearing potential
h
Performed at Screening Visit and Safety Follow-Up Visit only
Blood and urine samples for the clinical safety laboratory tests will be collected as outlined in 
Panel 2.
The blood and urine sampling and handling procedures are described in the study-specific 
Laboratory Specification Manual.
It is mandatory for blood and urine samples to be analysed by the central laboratory. If 
necessary, for logistical reasons and per the investigator’s discretion, a local laboratory may 
also be used at the Baseline Visit. Central laboratory results supersede local laboratory results. 
If central laboratory results are not available for the eligibility assessment, the local laboratory 
results may be used to confirm eligibility. In this case, these results will be recorded in the 
eCRF together with the local laboratory reference ranges.
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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 eptinezumab). A 
patient with a value that is out-of-range at the Completion Visit (Week 48/Visit 14) or 
Withdrawal Visit and considered clinically significant must be followed in accordance with 
usual clinical practice. If the clinically significant out-of-range clinical safety laboratory test 
value has not normalized or stabilized or a diagnosis or a reasonable explanation has not been 
established by the SFU Visit, the investigator must decide whether further follow-up visits are 
required (this may include an additional medical examination and/or additional blood 
sampling). Any out-of-range values followed after the last protocol-specified contact with the 
patient will be documented in the patient’s medical records.
9.6.3
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. The investigator must take 
responsibility for reviewing the findings.
Pulse rate and blood pressure will be measured using a standard digital meter. Pulse rate and 
blood pressure will be measured in the following order: supine, sitting, and standing after the 
patient has rested in each position for at least 3 minutes.
At IMP Visits, vital signs including body temperature will be assessed both prior to and after 
infusion. When coinciding, vital signs including body temperature must be assessed prior to 
blood sampling.
9.6.4
Height and Weight
The patient’s height will be measured once at the Screening Visit.
The patients will be weighed wearing light clothing and no shoes. A similar amount of 
clothing must be worn on each occasion. At IMP Visits, weight is assessed prior to infusion.
9.6.5
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 PR, QRS, QT, and QTc intervals.
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The ECG printout must be evaluated and signed by the investigator prior to eptinezumab
administration. The investigator has the final decision on the interpretation of the ECG 
results.
9.6.6
Physical and Neurological Examinations
Physical and neurological examinations for all clinic visits after the Screening Visit will be 
conducted at the discretion of the investigator. If these examinations are conducted at an IMP 
Visit, these must be performed prior to the infusion.
The investigator may appoint a designee to be primarily responsible for performing the 
physical and neurological examinations, such as physician assistant or nurse practitioner (as 
applicable), provided this is permitted according to local regulations. The investigator’s 
designee must be properly trained and have experience in performing these examinations. The 
investigator must take responsibility for reviewing the findings. Whenever possible, the same 
individual should perform all the physical examinations.
The physical examination must, at a minimum, include an examination of appearance, 
extremities, skin, head, neck, eyes, ears, nose, throat, lungs, chest, heart, abdomen (including 
the renal regions), and musculoskeletal system.
9.6.7
Columbia-Suicide Severity Rating Scale
The C-SSRS is a semi-structured interview developed to systematically assess suicidal 
ideation and behaviour of patients participating in a clinical study.52 The C-SSRS has 
5 questions addressing suicidal ideation, 5 sub-questions assessing the intensity of ideation, 
and 4 questions addressing suicidal behaviour. For this study, the following versions of the 
scale are used: the “Baseline/Screening” version (lifetime and 1-month assessment) and the 
“Since last visit” version (for all subsequent visits). It takes approximately 5 to 10 minutes to 
administer and rate the C-SSRS.
The C-SSRS must be administered in the local language.
The C-SSRS is a paper and pencil measure that should only be administered by a qualified 
rater and the investigator review must be documented in the patient’s medical records. 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. Any exceptions must be discussed and approved by Lundbeck and/or its 
designee.
Rater training and certification will be conducted by the CRO as agreed with Lundbeck. 
Raters will complete their designated training curriculum based on their initial qualification 
status and assigned role. Only raters who qualify on study-specific Rater Certification 
Programme will be authorised to administer the C-SSRS in the study. Documentation of 
training and certification will be provided to raters for archiving in the investigator site file 
and in the sponsor TMF. No patient must be rated before the documentation has been 
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archived. New raters joining the study must be trained and certified by using the same 
certification process. Detailed instructions on how to administer the C-SSRS will be provided 
to the clinical site in a C-SSRS Guideline.
9.6.8
Anti-Drug Antibody including Neutralizing Antibody Assessments
Blood samples for ADA, including NAb assessments (maximum total volume 15 mL), will be 
collected in accordance with Panel 2. The blood sampling and handling procedures are 
described in the study-specific Laboratory Specification Manual.
The serum samples will be analysed by a contracted laboratory under the responsibility of 
Department of Bioanalysis - Biologics, H. Lundbeck A/S, according to a protocol approved 
by Lundbeck.
9.7
Biobanking
9.7.1
General Considerations
This study includes collection of blood samples for long-term storage and use in a possible 
future explorative research study, that may help to increase our understanding of the aetiology 
of neurological diseases, such as migraine and the molecular basis of the drug response.
Although the potential future exploratory analyses will help to increase our understanding of 
the aetiology of cCH and the molecular basis of the drug response, the efforts described in this 
protocol are strictly research based. Therefore, as the complex interactions between genes and 
disease are currently not characterized to a level that translates to a meaningful clinical 
advantage, individual results from the exploratory analyses will not be given to either the 
study participants or the investigator. For the same reasons, individual results will not be 
added to the patients’ medical records.
The patients will have no direct benefit from the exploratory analyses.
To ensure privacy protection, the blood samples for RNA gene expression profiling, 
proteomics/metabolomics analysis and future ADA assessments will be single-coded using 
the patient’s screening number. The blood samples for the pharmacogenetic biomarker 
analysis will be double-coded, that is one code key will be stored at the clinical site and the 
other at Lundbeck. To link a DNA sample to a specific subject, both code keys are needed.
The blood samples collected for the possible future exploratory analysis may be shared with 
academic and public institutions and other companies. However, Lundbeck will retain full 
control of the samples and their use in accordance with the information in the Patient 
Information Sheet and a Material Transfer Agreement. Furthermore, the results based on the 
analysis of the samples may be pooled across studies to increase the statistical power of the 
analyses.
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9.7.2
Blood Sampling for Gene Expression Profiling
Blood samples for gene expression profiling will be collected in two PAXgene RNA tubes 
(2.5 mL) in accordance with Panel 2. The maximum volume of blood to be collected during 
the study for this purpose will be 15 mL.
Samples for gene expression profiling will be shipped to Lundbeck Biobank (at Brooks Life 
Sciences, Indianapolis, IN, USA) for storage. Sample preparation and analysis may be 
performed by the CRO or by a bona fide research collaborator.
9.7.3
Blood Sampling for Metabolomics and/or Proteomics
Blood samples for plasma separation and metabolomics and/or proteomics will be collected in 
one 10-mL K2 EDTA tube in accordance with Panel 2. The maximum volume of blood to be 
collected during the study for this purpose will be 30 mL.
Samples for gene expression profiling will be shipped to Lundbeck Biobank (at Brooks Life 
Sciences, Indianapolis, IN, USA) for storage. Sample preparation and analysis may be 
performed by the CRO or by a bona fide research collaborator.
9.7.4
Blood Sampling for Pharmacogenetics
It is optional for the patient to donate a blood sample for exploratory pharmacogenetic 
analysis.
Blood samples for subsequent DNA extraction and aliquoting will be collected in 9 mL K3 
EDTA tube in accordance with Panel 2. The maximum volume of blood to be collected 
during the study for this purpose will be 9 mL.
The extracted DNA aliquots will be shipped to Lundbeck Biobank (at Brooks Life Sciences, 
Indianapolis, IN, USA) for storage. Sample preparation and analysis may be performed by the 
CRO or by a bona fide research collaborator.
The genetic variants to be analysed may include single nucleotide polymorphisms and copy 
number variations. The analytical methods may be polymerase chain reaction (PCR), 
quantitative PCR, sequencing, or whole genome scans on microarrays.
9.7.5
Blood Sampling for Possible Future Anti-Drug Antibody Assessments
Whole blood samples for serum separation and potential future anti-eptinezumab antibody 
analyses will be collected in accordance with Panel 2. The maximum volume of blood to be 
collected during the study for this purpose will be 15 mL.
The samples for future ADA assessments will be shipped to Lundbeck Biobank (at Brooks 
Life Sciences, Indianapolis, IN, USA) for storage. Sample preparation and analysis may be 
performed by the CRO or by a bona fide research collaborator.
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9.8
Order of Assessments
At each IMP Visit (Day 0/Visit 2, Week12/Visit 5, Week 24/Visit 8, Week 36/Visit 11), prior
to eptinezumab infusion:
Patients must complete the eDiary and ePROs. ePROs must be completed before blood and 
urine sampling.
Vital signs must be assessed prior to blood sampling.
The following assessments must be conducted: vital signs (including body temperature), 
weight, concomitant medications, adverse events, physical and neurological examination 
(if done at the discretion of the investigator), ECG, blood sampling and urine sampling and 
C-SSRS administration.
At each IMP Visit (Day 0/Visit 2, Week12/Visit 5, Week 24/Visit 8, Week 36/Visit 11),
during eptinezumab infusion: patients must be monitored for adverse events.
At each IMP Visit (Day 0/Visit 2, Week12/Visit 5, Week 24/Visit 8, Week 36/Visit 11), after
end-of-eptinezumab-infusion, before the patient is discharged from the clinical site:
Patients must be monitored for at least 1 hour.
The following assessments must be conducted: vital signs including body temperature, and 
the patient must be monitored for adverse events. Vital signs must be assessed prior to 
blood sampling.
A blood sample for exploratory eptinezumab quantification and exploratory biomarkers 
must be taken within approximately 1 hour after end of infusion.
ePROs:
ePROs which are scheduled in alignment with a clinic visit:
can be completed in the clinic or in the remote setting within 3 days prior to the 
scheduled clinic visit date. On the day of IMP Visits (Day 0/Visit 2, Week 12/Visit 5, 
Week 24/Visit 8, and Week 36/Visit 11), patients must complete the ePROs prior to 
infusion and prior to any interaction with the clinical site staff.
ePROs which are scheduled in alignment with a phone contact:
must be completed in the remote setting and can be completed on the day or within 
3 days prior to the scheduled phone contact date.
It is preferable that the scheduled time of the day for the assessments is as consistent as 
possible across all the study visits.
9.9
Total Volume of Blood Drawn and Destruction of Biological Material
The total volume of blood drawn from each patient will be approximately 221.5 mL during 
the study.
Additional blood samples may be required if the original blood samples are not viable or if 
re-testing is required.
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After analysis, all remaining serum or plasma samples will be stored at -20°C for a minimum 
of one year. Whole blood and urine sediment samples will be stored for a minimum of one 
week. The central laboratory will be notified by Lundbeck when the biological samples may 
be destroyed.
The biobank blood samples and any derived material for potential future exploratory gene 
expression profiling, metabolic or proteomic biomarker analyses, or ADA assessments will be 
destroyed ≤10 years after the end of the study (see definition in section 8.10).
9.10
Treatment Compliance
Responsible study personnel will administer the infusions of eptinezumab. Treatment 
compliance verification should be documented in the patient’s source documents and 
study-specific eptinezumab documents and verified by a CRA during monitoring.
Anyone administering eptinezumab to the patient must be listed in the delegation log.
The information from the IMP Administration Form must be entered in the eCRF.
10 Adverse Events
10.1
Definitions
10.1.1
Adverse Event Definitions53
Adverse event – is any untoward medical occurrence in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment.
An adverse event can therefore be any unfavourable and unintended sign (including clinically 
significant out-of-range values from relevant tests, such as clinical safety laboratory tests, 
vital signs, ECGs), symptom, or disease temporally associated with the use of a medicinal 
product, regardless of whether it is considered related to the medicinal product.
A worsening of a pre-existing or chronic condition is considered an adverse event and must be 
reported as such. Medical conditions, which existed prior to the time of informed consent into 
the clinical study are part of the patient's medical history and are not considered an adverse 
event. Unchanged, chronic, non-worsening or pre-existing conditions from the time of 
informed consent are not adverse events and should not be reported as such.
Adverse events (serious and non-serious) must be collected, recorded, and reported to 
Lundbeck from the time the patient has signed the Informed Consent Form(s) at the Screening 
Visit until the Safety Follow-up Visit.
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Serious adverse event – is any adverse event that:
results in death
is life-threatening (this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
had it been more severe)
requires inpatient hospitalisation or prolongation of existing hospitalisation
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 hospitalisation, 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 hospitalisation; or development of drug 
dependency or drug abuse.
Planned hospitalisations or surgical interventions for a condition that existed before the 
patient signed the Informed Consent Form(s) and that did not change in intensity are not 
adverse events. Emergency room visits that do not result in admission to the hospital are not 
necessarily SAEs; however, they must be evaluated to determine whether they meet any of the 
SAE definitions (for example, life-threatening or other serious [medically important] event).
Non-serious adverse event – is any adverse event that does not meet the definition of an SAE.
If there is any doubt as to whether an adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an SAE.
Suspected unexpected serious adverse reaction (SUSAR) – is any adverse event that is 
assessed as serious, unexpected (its nature or intensity is not consistent with the current 
version of the Investigator’s Brochure29), and related to a medicinal product by either the 
investigator or Lundbeck.
Overdose – is a dose received 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.
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Moderate – the adverse event is sufficiently uncomfortable to produce some impairment of 
the patient’s normal activities.
Severe – the adverse event is incapacitating, preventing the patient from participating in the 
patient’s normal activities.
Assessment of Causal Relationship
The investigator must assess the causal relationship between the adverse event and 
eptinezumab 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 eptinezumab or recurs 
on rechallenge, and another aetiology is unlikely or significantly less likely.
Possible – the adverse event has a suggestive temporal relationship to eptinezumab, and an 
alternative aetiology is equally or less likely.
Not related – the adverse event has no temporal relationship to eptinezumab or is due to 
underlying/concurrent disorder or effect of another drug (that is, there is no causal 
relationship between eptinezumab and the adverse event).
An adverse event is considered causally related to the use of eptinezumab 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.
Recovered with sequelae – the patient has recovered, but some symptoms remain (for 
example, the patient had a stroke and is functioning normally, but has some motor 
impairment).
Not recovered – the patient’s condition has not improved, and the symptoms are 
unchanged (for example, an atrial fibrillation has become chronic).
Death.
10.1.3
Management of Reactions to Study Drug
There are no specific antidotes to an infusion of eptinezumab.
A medical emergency should be treated appropriately by the investigator using proper 
standard of care, according to their typical clinical practice and local guidelines for that 
emergency condition.
Should a medical condition arise that the investigator believes is related to the study drug, 
clinical judgement should be used to provide the appropriate response including the 
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consideration of discontinuation of study drug. If a patient experiences an anaphylactic 
reaction or another severe and/or serious hypersensitivity reaction during eptinezumab
infusion, as assessed by the investigator, the infusion must be discontinued immediately (see 
section 6.2) and appropriate therapy instituted. Any events believed to be allergic reactions 
should be discussed with the medical monitor.
The clinical site will have the possibility to collect, at the time of the event, additional blood 
specimens using the immune response lab kit, per the laboratory manual. This assessment 
includes serum histamine, serum tryptase, immunoglobulin E, and complement components.
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.
Once completed, Pregnancy Form (paper) shall be sent to:
Fax:
+45 36 30 99 67
email:
ICSRquery@lundbeck.com
If sent by email, the investigator must ensure that the Pregnancy Form is sent password 
protected and that the password is sent in a separate email.
An uncomplicated pregnancy should not be reported as a SAE; hospitalisation for a normal 
birth should not be reported as an SAE. If, however, the pregnancy is associated with a SAE, 
the appropriate serious criterion must be indicated on the Serious Adverse Event Form. 
Examples of pregnancies to be reported as SAEs (medically important) are spontaneous 
abortions, stillbirths, and malformations.
The investigator must follow up on the outcome of the pregnancy and report it on a 
Pregnancy Form (paper). The follow-up must include information on the neonate at least up 
until the age of 1 month.
If required by local regulations, the patient and her partner will be asked to sign a separate 
Informed Consent Form in case of pregnancy.
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 or occurs on the day of eptinezumab
administration); intensity; causal relationship to eptinezumab; action taken; and outcome. If 
the adverse event is not related to eptinezumab, an alternative aetiology must be recorded, if 
available. If the adverse event is an overdose, the nature of the overdose must be stated (for 
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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 within the eCRF 
Rave®.
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
When Rave is available again, the site must enter the SAE information into Rave.
If sent by email, the investigator must ensure that the SAE Fallback Form is sent password 
protected and that the password is sent in a separate email.
Lundbeck will assume responsibility for reporting SAEs to the authorities in accordance with 
local requirements.
It is the investigator’s responsibility to be familiar with local requirements regarding reporting 
SAEs to the EC or IRB and to act accordingly.
Lundbeck will assume responsibility for reporting SUSARs to the authorities in accordance 
with local requirements. In those Member States of the European Union that have 
implemented the European Union Clinical Trials Directive54, 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 SUSAR listings.
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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.
Non-serious adverse events must be followed up until resolution or the SFU Visit, whichever 
comes first. At the SFU Visit, information on new adverse events, if any, and stop dates for 
previously reported adverse events must be recorded.
The investigator must follow up on all SAEs until the patient has recovered, stabilized, or 
recovered with sequelae, and report to 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 SFU Visit must 
be handled in the same manner as SAEs that occur during the study considering relation to 
IMP. 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 Completion Visit (Week 48/Visit 14) or Withdrawal Visit in 
accordance with usual clinical practice. If the clinically significant out-of-range clinical safety 
laboratory test value has not normalized or stabilized or a diagnosis or a reasonable 
explanation has not been established by the SFU Visit, the investigator must decide whether 
further follow-up visits are required (this may include an additional medical examination 
and/or additional blood sampling). If further follow-up visits are made, these must be 
documented in the patient’s medical records and not in the eCRF.
Patients who withdraw due to an elevated AST or ALT value (see section 6.2) must be 
followed until the values normalize or stabilize or a diagnosis or a reasonable explanation has 
been established. Additional medical examinations (for example, ultrasound scanning and/or 
sampling for serology, conjugated bilirubin, prothrombin time) should be considered. A 
gastroenterology or hepatology consultation should also be considered.
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 
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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 Lundbeck and/or representatives from the CRO. All 
entries, corrections, and changes must be made by the investigator or a delegate.
11.1.2
Patient Binders
11.1.2.1
Use of Patient Binders
A Patient Binder will be provided for each patient. The Patient Binder contains different 
types of source documents, organised by visit and type. A ballpoint pen with waterproof ink 
must be used to enter information in the Patient Binder.
11.1.2.2
Serious Adverse Event Fallback Forms
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed.
11.1.3
External Data
All electronic data will be transferred by the designated vendor and kept in a secure 
designated storage area outside the eCRF:
eDiary data
ePRO data
ECG results
Clinical safety laboratory data
Biobanking data: RNA, metabolomics/proteomics, ADA including NAb, DNA (optional)
Biomarker analysis results
Eptinezumab quantification results
11.2
Retention of Study Documents at the Clinical Site
11.2.1
eCRF Data
If a site closes before the study has been completed, the investigator will continue to have 
read-only access to the eCRF until the study has been completed. After the study has been 
completed, all user access to the eCRF will be revoked. Renewed access to the eCRF will be 
given if corrections or updates to the database are required.
At the end of the study, the clinical site will be provided with all data related to the clinical 
site (including eCRF data, queries, and the audit trail) using a secure electronic medium; the 
secure storage of these data at the clinical site is the responsibility of the investigator. When 
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confirmation of receipt of the data has been received from all sites, all user access to the 
eCRF will be revoked. If, for some reason, the data are not readable for the full retention 
period (25 years or in accordance with national requirements, whichever is longer), the 
investigator may request that the data be re-sent.
11.2.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator site file 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 clinical site.
If off-site storage is used, a study-specific binder will remain at the clinical site after the other 
study-specific documents have been shipped for off-site storage. This binder is considered 
part of the investigator site file and must be kept in a secure place by the clinical site for the 
required period of time. The binder must contain, at a minimum, the following documents: a 
copy of the Investigator Site File 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 
clinical site. The document will also list which data may be recorded directly on the eCRFs.
Only patients with cCH may be enrolled in the study. The patient’s medical records are the 
most comprehensive source to document the patient’s diagnosis. Thus, it is required that the 
investigator obtains copies of medical records for each patient. In case the investigator does 
not have medical records for a patient at his/her own clinic, the investigator must obtain 
copies/written summary of relevant medical records from the previous treating physician and 
include the pertinent documentation in the patient’s medical records at the clinical site. If 
original medical records are unavailable, any properly documented communication with the 
treating physician, letters, written summaries, photocopies of medical records, pharmacy 
records and specific letter templates may be used to document the cCH diagnosis and 
previous acute medication use for cCH, covering a period of at least 12 months prior to the 
Screening Visit and general medical history prior to the study. Information about changes in 
the patient’s medical history, treatment for cCH and other concomitant medication that might 
occur between the Screening Visit and the Baseline Visit must be obtained, using the above 
described modalities and documented in the patient’s medical records at site.
During the study, the CRA will visit the clinical site to ensure that the protocol is being 
adhered to and that all issues are being recorded, to perform source data verification, and to 
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monitor IMP accountability. The visit intervals will depend on the outcome of the remote 
monitoring of the eCRFs, the clinical site’s recruitment rate, and the compliance of the 
clinical 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.
Due to COVID-19, if the clinical site is closed to the CRO’s monitor for safety measures, 
remote source data verification may be done in exceptional cases, if allowed per local and site 
regulations.
13 Audits and Inspections
Authorised personnel from Medical, Regulatory and Clinical Quality Assurance, 
H. Lundbeck A/S, and quality assurance personnel from business partners may audit the study 
at any time to assess compliance with the protocol and the principles of Good Clinical 
Practice and all other relevant regulations.
The investigator must be aware that representatives from regulatory authorities may also wish 
to inspect source data, such as medical records. The investigator must notify Lundbeck, 
without delay, of an announced inspection by a regulatory authority.
During audits and inspections, the investigator must permit direct access to all the source 
documents, including medical records and other documents pertinent to the study.
During audits and inspections, the auditors and inspectors may request relevant parts of 
medical records. No personal identification apart from the screening numbers will appear on 
these copies.
Patient data will not be disclosed to unauthorised third parties, and patient confidentiality will 
be respected at all times.
14 Protocol Compliance
Lundbeck has a “no-waiver” policy, which means that permission will not be given to deviate 
from the protocol.
If a deviation occurs, the investigator must inform the CRA and they must review, discuss, 
and document the implications of the deviation.
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15 Study Termination
Lundbeck or a pertinent regulatory authority may terminate the study or part of the study at 
any time. The reasons for such action may include, but are not limited to:
safety concerns;
proven lack of efficacy of anti-CGRP agents in clinical studies sponsored by Lundbeck or 
competitors.
If the study is terminated or suspended, the investigator must promptly inform the patients 
and ensure appropriate therapy and follow-up. Furthermore, the investigator and/or Lundbeck 
must promptly inform the EC or IRB and provide a detailed written explanation. The 
pertinent regulatory authorities must be informed in accordance with national regulations.
If the risk/benefit evaluation changes after the study is terminated, the new evaluation must be 
provided to the EC or IRB if it will have an impact on the planned follow-up of the patients 
who participated in the study. If so, the actions needed to protect the patients must be 
described.
16 Statistical Methodology
16.1
Responsibilities
Biostatistics, H. Lundbeck A/S will perform the statistical analyses for the Clinical Study 
Report.
16.2
Analysis Sets
The following analysis sets will be used to analyse and present the data:
all-patients-enrolled set (APES) - all-patients-enrolled
all-patients-treated set (APTS) - all patients in the APES who receive infusion with 
eptinezumab
full-analysis set (FAS) - all patients in the APTS who have a valid assessment of the
baseline number of monthly attacks and a post-baseline assessment of number of monthly 
attacks
The safety and tolerability analyses, and the exposure, disposition, and demographics and 
baseline characteristics will be based on the APTS. The efficacy analyses will be based on the 
FAS.
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.
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16.4
Patient Disposition
Patient disposition will be summarised and include the number of patients in the APTS who 
completed or withdrew from treatment, as well as the number of patients in each analysis set 
(APES, APTS, and FAS).
The number of patients who withdrew from the study will be summarised by primary reason 
for withdrawal and all reasons for withdrawal.
16.5
Demographics and Baseline Characteristics
Demographics (sex, age, and race), baseline characteristics (height, weight, and BMI), 
baseline efficacy variables, and other disease characteristics will be summarised by visit.
16.6
Recent and Concomitant Medication
Recent and concomitant medication will be summarised by anatomical therapeutic chemical 
(ATC) code and generic drug name by visit.
16.7
Exposure and Compliance
Exposure and compliance will be calculated per patient and summarised by visit.
The number of patients infused and patients who had their infusion interrupted will be 
summarised by visit. Patients whose infusion took more than 60 minutes and patients who had 
their infusion interrupted will be listed with period, infusion start date/time and end date/time, 
and reasons if any.
16.8
Efficacy Analyses
16.8.1
General Efficacy Analysis Methodology
All confidence intervals (CIs) will be 95% CIs, unless otherwise specified.
Baseline number of weekly attacks will be derived from eDiary data collected in the 
Screening Period (Week -4 to Day 0).
16.8.2
Analysis of the Secondary Endpoints
Details on derivations and imputations of eDiary data (daily or weekly data entries), as well as 
sub-group analyses, will be described in the Statistical Analysis Plan (SAP).
For continuous endpoints, descriptive statistics for absolute values and change from baseline 
when appropriate will be provided by visit. In addition, continuous endpoints will be 
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modelled using mixed models for repeated measurements (MMRM) including baseline score, 
visit and baseline interacting with visit, if applicable.
The estimated means, standard errors and CIs will be provided by visit. For response variables 
the counts, percentages and CI will be presented by visit.
16.8.3
Testing Strategy
No formal testing will be done.
16.9
Safety Analyses
The primary objective of the study is to evaluate the long-term safety and tolerability of 
eptinezumab in patients with cCH. This will be evaluated based on the collected data on 
adverse events, vital signs, weight, ECGs, clinical safety laboratory test values, C-SSRS, 
ADA and NAbs.
16.9.1
Analysis of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:
pre-treatment adverse event – an adverse event that starts on or after the date the patient 
signed the Informed Consent Form(s) and prior to the date of first dose of eptinezumab
treatment-emergent adverse event (TEAE) – an adverse event that starts or increases in 
intensity during or after administration of the first dose of eptinezumab
Adverse events, sorted by system organ class (SOC) and preferred term, will be summarised 
for the full study and by 3-month periods.
Allocation of TEAEs to Study Periods
TEAEs may be allocated to study periods (these will be defined in the Statistical Analysis 
Plan).
16.9.2
Analysis of Other Safety Endpoints
Absolute values and change from baseline for vital signs, weight, ECGs, clinical safety 
laboratory test values will be summarised by visit. The number of patients exceeding the PCS 
values will be tabulated. The incidence, kinetics and magnitude of ADA and NAb response(s) 
will be evaluated.
16.10 Interim Analyses
No interim analysis is planned.
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16.11 Sample Size and Power
In line with the ICH E1 guideline,1 the study aims at providing data in 100 patients exposed to 
eptinezumab for 1 year. Dodick (2020),2 in patients suffering from cCH included in a 
12-week study, reports less than 4% withdrawals. In the European Union Drug Regulating 
Authorities Clinical Trials (EudraCT) report for study NCT02964338,3 in patients suffering 
from cCH, approximately 7% of patients dropped out from the first 12-week period; the 
withdrawals due to the “sponsor terminated study” are not included as a reason for 
withdrawal. As the withdrawal rate for a long-term study like the current study is unknown, 
125 patients are planned to be enrolled and treated, allowing for 100 patients to complete, 
with a withdrawal rate of 20%. The withdrawal rate will be monitored during the study 
conduct, and if a clear deviation from the assumed withdrawal rate is observed, the number of 
patients enrolled and treated might be increased to ensure that data is available for a sufficient 
number of patients with long-term exposure.
16.12 Statistical Analysis Plan
A Statistical Analysis Plan describing the handling of data issues and the planned statistical 
analyses in more detail will be prepared by Biostatistics, H. Lundbeck A/S.
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 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, in accordance with the Lundbeck 
policy and regardless of the study outcome.
Lundbeck will submit results information:
to ClinicalTrials.gov
to EudraCT
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The primary publication based on this study must be published before any secondary 
publications. Authors of the primary publication must fulfil the criteria defined by the 
International Committee of Medical Journal Editors (ICMJE).55
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 clinical site are addressed in one or more documents. 
Both parties must sign the agreements before each site is initiated.
19.2
Financial Disclosure
All the investigators, including sub-investigators, and raters participating in the study must 
complete a Financial Disclosure Form.
19.3
Equipment
Equipment owned or rented by Lundbeck that will be provided to the clinical sites for use 
during the study must be returned at the end of the study.
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44. Caceres MC, Guerrero-Matin J, Pérez-Civantos D, Palomo-Lopez P, Delgado-Mingorance JI, 
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48. Lipton RB, Micieli G, Russel G, Solomon S, Tfelt-Hanse P, Waldenlind E. The IHS Members’ 
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Appendix I
Clinical Study Protocol
Authentication and Authorisation
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Clinical Study Protocol
Authentication and Authorisation
Study title:
Interventional, open-label, fixed-dose multiple administration study to evaluate 
long-term treatment with eptinezumab in patients with chronic cluster headache
Study No.:
19385A
Edition No.:
2.0
Date of edition:
25 November 2021
This document has been signed electronically. The signatories are listed below.
Authentication
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
International study manager:
Clinical research scientist:
Head of Biostatistics:
Head of Medical Safety:
Authorisation
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
Therapeutic Area Lead:
Bjørn Sperling
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 
Anticonvulsants can only be used for preventive treatment for cluster 
headache and are allowed with restrictions- see Cluster Headache 
Therapies.
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Cluster Headache Therapies
Abortive treatment
The following abortive therapies for cluster headache attack are allowed
at any time during the study:
High-flow oxygen;
Oral triptans, sumatriptan subcutaneous injection; sumatriptan nasal 
spray; zolmitriptan nasal spray;
Acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs);
Dihydroergotamine (allowed for not more than 3 times per week) or 
ergot derivatives;
Octreotide.
Opioids are allowed with restrictions (maximum 2 days per week).
Cannabinoids are allowed if prescribed or if locally approved
Transitional treatment
Disallowed for 30 days prior to the Screening Visit and during the 
Screening Period:
Greater occipital nerve block;
Injected and oral steroids (used for headache treatment).
Preventive treatment:
Stable dose (with restriction on the maximum dose for lithium only) for 
1 month prior to the Screening Visit and during the Screening Period:
Verapamil;
Topiramate;
Gabapentin;
Valproate;
Candesartan;
Lithium: the maximum dose must be as per the country-specific 
guidelines for management of patients with CH AND the se-lithium 
level must be below the toxic serum level of lithium, based on the 
reference ranges of the local laboratory;
Indomethacin.
Initiation, discontinuation, and change of dose are allowed during the 
Treatment Period and the SFU Period.
At any time:
Melatonin
Initiation, discontinuation, and dose modifications are allowed during 
the Treatment Period and the SFU Period.
Dihydroergotamine is disallowed for use as a preventive treatment.
Other treatment and interventions:
Disallowed for 4 months prior to the Screening Visit and until the SFU
Visit:
Botulinum toxin type A or B, administered in the head or neck area 
for treatment of cluster headache or other disorders, or for cosmetic 
use.
Disallowed for 30 days prior to the Screening Visit and until the SFU
Visit:
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Drug Class
Details
any other cranial or extracranial nerve block;
any neuromodulation treatment;
gamma knife or other invasive procedures.
Anti-CGRP therapies
Anti-CGRP therapies are disallowed for ≤5 half-lives for mAbs and 
≤1 month for gepants prior to the Screening Visit.
Antihypertensives 
Candesartan and Verapamil allowed with restrictions- see Cluster 
Headache Therapies
Other medications in the same class are allowed.
Anti-impotence agents
Allowed if the dose has been stable for at least 12 weeks prior to the 
Screening Period and remains stable until the Completion Visit 
(Week 48).
Cannabinoids
Allowed with restrictions- see Cluster Headache Therapies.
COVID-19 vaccine
Allowed with restrictions:
If possible, COVID-19 vaccine should not be administered <14 days 
prior to the Screening Visit.
If possible, COVID-19 vaccine should not be given within ±3 days of 
eptinezumab infusion.
Ergot alkaloids 
Methergine is disallowed for 14 days prior to the Screening Visit and 
until the SFU Visit.
Other medications in the same class are allowed.
Steroids:
Oral and Injectable
Allowed with restrictions:
For transitional treatment for CH, see Cluster Headache Therapies
For indications other than cluster headache: 
i.
Disallowed during the Screening Period
ii.
Short-term treatment (maximum 3 days, followed by potential 
tapering) is allowed from Baseline until the SFU Visit
Illicit substances 
Disallowed for 2 months prior to the Screening Visit and until the SFU 
Visit: Psilocybin (mushrooms), lysergic acid diethylamide (LSD), or 
2-bromo-LSD, or other illegal drugs.
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