Clinical trial NCT05064397
Conditions: Chronic Cluster Headache
Sponsor: H. Lundbeck A/S
Start date: 2021-09-17; Completion date: 2023-06-29
Enrollment: 131 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main goal of this trial is to inform about long-term safety and tolerability of eptinezumab in participants with chronic cluster headache.

Detailed description:
The participants who take part in this trial will be asked to stay in the trial for about a year. The participants will be asked to visit the trial site 7 times during the trial. In between trial site visits, they will have scheduled phone calls with the trial site staff. They will also be asked to keep track of their cluster headaches at home with a headache diary.

Arms: arm 1: Participants will receive 4 intravenous (IV) infusions with eptinezumab at Baseline (Day 0) and at the end of Weeks 12, 24, and 36.
Interventions: intervention 1: Eptinezumab
Intervention descriptions: intervention 1: Eptinezumab will be administered per schedule specified in the arm description.

Protocol documents:
SAP_002.pdf: 
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Statistical Analysis Plan
Interventional, open-label, fixed-dose multiple administration 
study to evaluate long-term treatment with eptinezumab in 
participants with chronic cluster headache
Eptinezumab
Trial No.:
19385A
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
SAP date:
29 June 2023
This document is the property of H. Lundbeck A/S and H. Lundbeck A/S is the holder of any and all 
related intellectual property rights, including, but not limited to, copyrights.  This document is 
confidential.  It is not to be copied or distributed to other parties without prior written authorization 
from H. Lundbeck A/S.
PPD
PPD
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Table of Contents
List of Panels and Tables...............................................................................................................6
List of Abbreviations and Definitions of Terms ..........................................................................7
1
Objectives...............................................................................................................................8
1.1
Primary Objective........................................................................................................8
1.2
Secondary Objectives ..................................................................................................8
1.3
Exploratory Objective..................................................................................................8
2
Trial Design............................................................................................................................8
3
Definitions ............................................................................................................................10
3.1
Definition of Baseline................................................................................................10
3.2
Definition of Periods..................................................................................................10
3.3
Definition of Withdrawal...........................................................................................11
3.4
Definition of a Month ................................................................................................11
4
COVID-19 ............................................................................................................................11
5
Endpoints..............................................................................................................................11
6
Analysis Sets.........................................................................................................................14
7
Descriptive Statistics ...........................................................................................................15
8
Participant Disposition........................................................................................................15
8.1
Summary of Participant Disposition..........................................................................15
8.2
Withdrawals...............................................................................................................15
9
Demographics and Baseline Characteristics.....................................................................16
10
Recent and Concomitant Medication ................................................................................17
11
Exposure...............................................................................................................................18
12
eDiary Compliance ..............................................................................................................18
13
Efficacy.................................................................................................................................18
13.1
General Efficacy Analysis Methodology...................................................................18
13.2
Testing Strategy.........................................................................................................18
13.3
Analysis Methodology for the Primary Endpoints ....................................................19
13.4
Analysis Methodology for the Key Secondary Endpoints.........................................19
13.5
Analysis Methodology for the Secondary and Exploratory Endpoints......................19
13.5.1
Short-term Efficacy Estimand....................................................................19
13.5.1.1
Rationale for the Short-term Efficacy Estimand........................19
13.5.1.1.1
Missing Data ..........................................................20
13.5.1.2
Estimator....................................................................................21
13.5.2
Additional Short-term Efficacy Estimand..................................................21
13.5.3
Long-term Efficacy Estimand ....................................................................21
13.5.4
Rationale for the Efficacy Endpoints following the strategy of the Long-
term Efficacy Estimand..............................................................................22
13.5.5
Intercurrent Events and Withdrawal from Treatment ................................23
13.5.6
Efficacy Analysis .......................................................................................23
13.5.6.1
Continuous Efficacy Endpoints .................................................23
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13.5.6.2
Efficacy Endpoints Regarding Response...................................25
13.5.6.3
Other Efficacy Endpoints...........................................................26
13.5.6.4
Subgroup Analyses ....................................................................26
13.5.7
Rationale for Selected Analysis Method for the Secondary and Exploratory 
Endpoints....................................................................................................26
13.5.8
eDiary Reported Use of Medication...........................................................26
13.5.9
Sensitivity Analyses of Secondary and Exploratory Endpoints.................26
13.5.9.1
Sensitivity Analyses to assess the impact of the use of 
transitional medication...............................................................26
13.5.9.2
Sensitivity Analyses to assess the impact of the strategy of 
handling withdrawal from treatment..........................................26
13.5.9.3
Sensitivity Analyses to assess the impact of missing data 
regarding response .....................................................................27
14
Safety ....................................................................................................................................27
14.1
Adverse Events..........................................................................................................27
14.1.1
General Methodology for Adverse Events.................................................27
14.1.2
Coding of Adverse Events..........................................................................27
14.1.3
Classification of Adverse Events ...............................................................27
14.1.4
Presentation of Adverse Events..................................................................28
14.1.5
Presentation of Treatment-emergent Adverse Events ................................28
14.1.6
Presentation of Deaths................................................................................28
14.1.7
Presentation of Serious Adverse Events.....................................................28
14.1.8
Presentation of Adverse Events Leading to Withdrawal............................29
14.1.9
Presentation of Adverse Events leading to Trial Drug Infusion Interruption 
or Termination............................................................................................29
14.1.10
Presentation of Adverse Events of Special Interest....................................29
14.2
General Methodology for Other Safety Data.............................................................29
14.3
Clinical Safety Laboratory Test Data ........................................................................30
14.3.1
Data Presentation........................................................................................30
14.3.2
Potential Drug-induced Liver Injury (DILI)...............................................30
14.4
Vital Signs and Weight..............................................................................................31
14.5
ECGs..........................................................................................................................31
14.6
Other Safety Endpoints..............................................................................................32
14.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores.......................32
15
Immunogenicity ...................................................................................................................33
16
Biomarker ............................................................................................................................33
17
Pharmacokinetic/Pharmacodynamic Analyses.................................................................34
18
Data Reviews........................................................................................................................34
19
Interim Analyses..................................................................................................................34
20
Sample Size Considerations................................................................................................34
21
Statistical Software..............................................................................................................35
22
Changes to Analyses Specified in the Protocol..................................................................35
23
Details on Data Handling....................................................................................................36
23.1
Data Structure............................................................................................................36
23.2
Derived Variables ......................................................................................................37
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23.2.1
eDiary.........................................................................................................37
23.2.1.1
The 5-point Self-rated Pain Severity Scale Scores ....................37
23.2.1.2
Calculation of Baseline eDiary Assessments.............................37
23.2.1.3
Imputation of Missing Post-baseline eDiary Assessments ........38
23.2.1.4
Assigning Week to eDiary Assessments....................................39
23.2.1.5
Calculation of Assessments for Intercurrent Events..................40
23.2.1.6
Calculation of Assessments for Sensitivity Analyses................40
23.2.1.7
Response....................................................................................40
23.2.1.8
Conversion from cCH to eCH....................................................41
23.2.1.9
Remission...................................................................................41
23.2.2
1-year Exposure..........................................................................................41
23.2.3
Country.......................................................................................................41
23.2.4
Use of Transitional Treatment....................................................................41
23.2.5
Treatment Failure .......................................................................................42
23.2.6
Treatment Resistant....................................................................................42
23.2.7
Sustained Response....................................................................................42
23.2.8
Maximum Score of Severity of Pain ..........................................................42
23.2.9
Patient Global Impression of Change (PGIC)............................................42
23.2.10
Sleep Impact Scale (SIS)............................................................................42
23.2.11
Euroqol 5 Dimension – 5 Levels (EQ-5D-5L)...........................................43
23.2.12
Health Care Resource Utilization (HCRU)................................................43
23.2.13
Work Productivity and Activity Impairment: General Health version 2 
(WPAI:GH2.0)...........................................................................................43
23.2.14
Withdrawal from Treatment.......................................................................44
23.3
Assigning Data to Visits ............................................................................................44
23.3.1
Clinical Outcome Assessments (COAs) - Scales .......................................45
23.3.2
Safety Variables .........................................................................................46
23.4
Handling Missing or Incomplete Dates/Times ..........................................................48
23.4.1
Withdrawal Date ........................................................................................48
23.4.2
Medical Disorder Start and Stop Dates ......................................................48
23.4.3
Medication Start and Stop Dates................................................................48
23.4.4
Adverse Event Start and Stop Dates...........................................................48
23.5
Data with Multiple Records.......................................................................................50
23.5.1
Dose Changes in Medication......................................................................50
23.5.2
Treatment-emergent AEs and Changes in Intensity or Seriousness of 
Adverse Events...........................................................................................50
References .....................................................................................................................................52
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Appendices
Appendix I
Statistical Analysis Plan Authentication and Authorization ..............................53
Appendix II
SAS® Code.........................................................................................................55
Appendix III
PCS Criteria .......................................................................................................57
Appendix IV
Trial flow chart...................................................................................................61
Appendix V
Adverse Events of Special Interest ....................................................................67
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List of Panels and Tables
Panel 1
Trial Design .............................................................................................................. 10
Panel 2
Endpoints.................................................................................................................. 12
Panel 3
Categories for baseline disease characteristics ......................................................... 16
Panel 4
C-SSRS Scores ......................................................................................................... 32
Panel 5
Definitions of Post-Baseline Pain Scores ................................................................. 39
Panel 6 
Windowing of Weeks – Weekly eDiary Assessments.............................................. 39
Panel 7
Derivation of WPAI:GH2.0 sub-scores.................................................................... 44
Panel 8
Visit Windows – PGIC ............................................................................................. 45
Panel 9
Visit Windows – SIS ................................................................................................ 45
Panel 10
Visit Windows – EQ-5D-5L, HCRU, and WPAI:GH2.0......................................... 45
Panel 11
Visit Windows – Laboratory tests, ECG .................................................................. 46
Panel 12
Visit Windows – Vital Signs (Pulse rate, Blood Pressure, Temperature)................. 47
Panel 13
Definition of Multiple Records................................................................................. 51
Table 1
PCS Criteria for Clinical Safety Laboratory Tests ................................................... 58
Table 2
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference .................... 60
Table 3
PCS Criteria for ECG Parameters............................................................................. 60
Table 4
Trial Procedures and Assessments............................................................................ 62
Table 5
Adverse Events of Special Interest........................................................................... 68
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List of Abbreviations and Definitions of Terms
ADA
Anti-drug antibody
AE
Adverse event
AESI
Adverse event of special interest
APES
all-participants-enrolled set
APTS
all-participants-treated set
BMI
body mass index
cCH
Chronic Cluster Headache
CGRP
calcitonin gene-related peptide
CH
Cluster Headache
CI
confidence interval
COA
Clinical outcome assessments
CS
Compound symmetry
C-SSRS
Columbia-Suicide Severity Rating Scale
DILI
drug-induced liver injury
ECG
electrocardiogram
eCRF
electronic case report form
ePRO
electronic participant-reported outcomes
EQ-5D-5L
Euroqol 5 Dimensions
FAS
Full-analysis set
HCRU
health care resource utilization
IMP
investigational medicinal product
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed model for repeated measurements
NAb
Neutralizing antibody
PCS
potentially clinically significant
PGIC
Patient global impression of change
SAE
serious adverse event
SAS®
statistical software package from the SAS® Institute
SE
standard error 
SFU
Safety Follow-up
SIS
Sleep Impact Scale
SOC
system organ class
TEAE
treatment-emergent adverse event
WPAI:GH2.0
Work Productivity Activity Impairment: General Health second version
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1
Objectives
1.1
Primary Objective
To evaluate the long-term safety and tolerability of eptinezumab in participants with chronic 
cluster headache (cCH).
1.2
Secondary Objectives
To evaluate the efficacy of eptinezumab in participants with cCH as well as the efficacy of 
eptinezumab on health-related quality of life, health care resource utilization, and work 
productivity.
1.3
Exploratory Objective
To explore the target engagement of eptinezumab to CGRP.
2
Trial Design
This is an interventional, open-label, fixed-dose multiple administration trial to evaluate the 
long-term treatment with eptinezumab in participants with cCH.
An overview of the trial is presented in Panel 1 and the scheduled trial procedures and 
assessments are summarized in Appendix IV.
The target population for this trial is defined as participants 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.
A minimum of 14 cluster headache attacks must be captured in the eDiary for the 28-day 
Screening Period.
The total trial 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 participants 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 of 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.
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Participants who withdraw from 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.
Participants who are withdrawn from the treatment will be given the opportunity to remain in 
the trial at the discretion of the investigator. Participants will be expected to attend all 
scheduled trial visits and procedures except eptinezumab administration. If participants 
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).
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 trial 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 participant-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.
Participants 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 trial 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.
Blood samples for exploratory eptinezumab quantification, and ADA and NAbs assessments 
will be collected at Weeks 0, 12, 24, 36 and 48 (or at Withdrawal Visit for participants, who 
withdraw from study) and at SFU Visit (Visit 15). Blood samples for exploratory biomarkers
will be collected at Weeks 0, 12, 24, 36 and 48 (or at Withdrawal Visit for participants, who 
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withdraw from study). ADA and NAbs will be collected before an IMP infusion. 
Furthermore, at each IMP visit, two blood samples will be collected for exploratory 
eptinezumab quantification and exploratory biomarkers; one sample prior to the eptinezumab 
infusion and one sample 1 hour after the end of the infusion.
Panel 1
Trial Design
3
Definitions
3.1
Definition of Baseline
For the efficacy endpoints based on the eDiary, e.g. the number of cluster headache attacks, 
the data collected during the first 28 days of the Screening Period will be used to calculate the 
baseline value for the endpoints. In case of a 7-day extension of the Screening Period, the last 
21 days of the original 28 days Screening Period and the first 7 days of the extension will be 
used to calculate the baseline value (if the extension is less than 7 days the days used prior to 
the extension should be changed accordingly ending up with a total of 28 days). Furthermore,
in case of re-screening, the baseline values will be calculated based on the first 28 days of the
re-screening period. See section 13.5.1.1.1 and chapter 23 for handling of missing data.
For the endpoints not based on the eDiary, the baseline value is the value captured either 
during the Screening Visit or at the Baseline Visit prior to the infusion, whichever is later.
3.2
Definition of Periods
The trial consists of the following periods:

Screening period (4 weeks): Starts at the Screening Visit and continues up to start of IMP 
infusion at the Baseline Visit
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
Treatment period (48 weeks): Starts at the IMP infusion at the Baseline Visit and continues 
up to and including the Completion Visit

Safety Follow-up period (8 weeks): Starts after the Completion Visit and continues up to 
and including the SFU Visit 
Unless otherwise specified, the Treatment Period, and the Safety Follow-up Period will be 
reported as one period.
3.3
Definition of Withdrawal 
Based on data captured in the eCRF we define the following categories of withdrawal:

Withdrawn from treatment

Withdrawn from study
Participants that do not withdraw from study, will be described as completing the study.
3.4
Definition of a Month
A Month is referring to a 28-day period.
4
COVID-19
For this trial, all participants are considered to have been enrolled after the beginning of the 
COVID-19 outbreak.
The following information is collected with regards to COVID-19:

Whether a visit was done remotely due to COVID-19 including which assessments 
were/were not performed

Whether participants withdrew due to the COVID-19 situation

Whether participants got diagnosed with COVID-19 
Remotely done visits will be tabulated or listed as appropriate. Participants diagnosed or 
withdrawn due to COVID-19 will be seen from tables/listings of AEs and AEs leading to 
withdrawal respectively.
5
Endpoints
The endpoints are summarized in Panel 2. There are no key secondary endpoints in this trial.
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Panel 2
Endpoints
Objectives
Endpoints
Primary Objective
To evaluate the long-term safety 
and tolerability of eptinezumab in 
participants with chronic cluster 
headache (cCH)
Primary endpoints:
- 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 (ADAs) 
including neutralizing antibodies (NAbs)
- Columbia-Suicide Severity Rating Scale (C-SSRS) score
Secondary Objectives
To evaluate the efficacy of 
eptinezumab in participants with 
cCH 
- Secondary endpoints:
- Change from Baseline in the number of weekly attacks (Weeks 1-4
and Weeks 1-2)
- Change from Baseline in the number of monthly attacks (Months 1-
12)
- Conversion from cCH to episodic cluster headache (eCH): no 
cluster headache attacks for ≥3 consecutive months (≥12
consecutive weeks) (Weeks 1-48)
- Change from Baseline in the weekly number of times an abortive 
therapy (oxygen and/or triptans where it will count as 2 times in 
case oxygen and triptans were used for the same attack) was used 
(Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 27, 28, 37, 38, 39, 40)
- Change from Baseline in the weekly number of times an abortive 
therapy (oxygen) was used (Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 
27, 28, 37, 38, 39, 40)
- Change from Baseline in the weekly number of times an abortive 
therapy (triptans) was used (Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 
27, 28, 37, 38, 39, 40)
- Change from Baseline in the number of weekly attacks (Weeks 1, 2, 
3, 4, 13, 14, 15, 16, 25, 26, 27, 28, 37, 38, 39, 40)
- Change from Baseline in the average attack related daily pain 
(including days with no attacks), as assessed using the 5-point self-
rating pain severity scale (Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 
27, 28, 37, 38, 39, 40)
- Response: ≥30% reduction from Baseline in the number of weekly 
attacks (Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 27, 28, 37, 38, 39, 
40)
- Response: ≥50% reduction from Baseline in the number of weekly 
attacks (Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 27, 28, 37, 38, 39, 
40)
- Response: ≥75% reduction from Baseline in the number of weekly 
attacks (Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 27, 28, 37, 38, 39, 
40)
- cCH remission: no cluster headache attacks for ≥1 month (≥4
consecutive weeks) (Weeks 1-48)
- cCH remission: no cluster headache attacks for ≥1 month (≥4
consecutive weeks) (Weeks 1-12, 13-24, 25-36, 37-48)
- Use of transitional treatment (Weeks 1-48)
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Objectives
Endpoints
To evaluate the efficacy of 
eptinezumab on health-related 
quality of life, health care resource 
utilization, and work productivity
- Patient Global Impression of Change (PGIC) score at Weeks 4, 8, 
…, 48
- Change from Baseline in the Sleep Impact Scale (SIS) domain 
scores at Weeks 4, 12, 16, 24, 28, 36, 40, 48
- Exploratory endpoints:
- Change from Baseline in the number of monthly attacks (Months 1,
2, …, 12)
- Change from Baseline in the pain per attack, as assessed using the 
5-point self-rating pain severity scale (Months 1, 2, …, 12)
- Response: ≥30% reduction from Baseline in the number of monthly 
attacks (Months 1, 2, …, 12)
- Response: ≥50% reduction from Baseline in the number of monthly 
attacks (Months 1, 2, …, 12)
- Response: ≥75% reduction from Baseline in the number of monthly 
attacks (Months 1, 2, …, 12)
- Response: 100% reduction from Baseline in the number of monthly 
attacks (Months 1, 2, …, 12)
- Change from Baseline in the monthly number of times an abortive 
therapy (oxygen and/or triptans, only oxygen, and only triptans) 
was used (Months 1, 2, …, 12)
- Change from Baseline in the weekly integrated measure of fre-
quency and intensity of attack related pain, that is, the sum of the 
intensity (worst pain on a 5-point self-rating pain severity scale) for 
each attack during a week (Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 
27, 28, 37, 38, 39, 40) or the intensity of attack related pain multi-
plied by the weekly number of attacks (Weeks 5, 6, …, 12, 17, 18, 
…, 24, 29, 30, …, 36, 41, 42, …, 48)
- Use of triptans (Weeks 1-48)
- Use of oxygen (Weeks 1-48)
- Use of preventive medication (Weeks 1-48)
- Sustained response: ≥75% reduction from Baseline in the number of 
monthly attacks for any month, where all the subsequent months 
also had ≥75% reduction from Baseline in the number of monthly 
attacks (Months 1, 2, …, 12)
- A maximum score of mild on the 5-point self-rating pain severity 
scale (Weeks 1, 2, …, 48)
- Secondary endpoints:
- Change from Baseline in the EuroQol 5-Dimension 5-Level (EQ-
5D-5L) score at Weeks 4, 16, 28, 40, and 48
- Health Care Resources Utilization (HCRU) at Baseline and 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
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Objectives
Endpoints
Exploratory Objective
To explore the target engagement 
of eptinezumab to calcitonin gene-
related peptide (CGRP)
Exploratory endpoint
- Change from Baseline in CGRP (CGRP-eptinezumab complex, free 
CGRP) at Weeks 12, 24, 36, and 48 
6
Analysis Sets
The following analysis sets will be used to analyse and present the data:

all-participants-enrolled set (APES) – all enrolled participants

all-participants-treated set (APTS) - all participants in the APES who received infusion 
with eptinezumab

full-analysis set (FAS) - all participants in the APTS who have a valid assessment of the 
baseline number of weekly attacks and a post-baseline assessment of number of weekly 
attacks.
The participants and data will be classified into the analysis sets during a Classification 
Meeting according to the definitions above after the trial database has been released, but prior 
to the headline results meeting.
Safety analyses (including tolerability and exposure), disposition, demographics and baseline 
characteristics will be based on APTS. 
Efficacy analyses will be based on FAS.
Three Data Point Sets (DPS) will be used for presenting the results using eDiary data:

DPS1: All data points obtained at or after enrolment

DPS2: All data points obtained at or after enrolment except for those following the 7-day 
rule after the use of transitional treatment (for details see section 23.2.4)

DPS3: All data points obtained at or after enrolment except for those following the 7-day 
rule after the use of transitional treatment (see section 23.2.4) and those following the 12-
week rule after withdrawal from treatment (see section 23.2.1.5)
DPS1 will be used for the descriptive statistics described in chapter 7 as well as the sensitivity 
analyses described in sections 13.5.9.1 and 13.5.9.2, DPS2 will be used for the short-term 
efficacy estimand described in section 13.5.1, and DPS3 will be used for the long-term 
efficacy estimand (section 13.5.3), the sensitivity analysis described in section 13.5.9.3, and
analyses based on eDiary data. For more details see chapter 13.
For efficacy data not derived from the eDiary all analyses will be based on all data points 
obtained at or after enrolment.
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7
Descriptive Statistics
Unless otherwise specified, summary statistics (numbers, arithmetic mean, standard deviation 
[SD], median, lower and upper quartiles, minimum and maximum values) will be presented 
for continuous variables, and counts and, if relevant, percentages will be presented for 
categorical variables.
Unless otherwise specified, data listings will include site, participant screening number, sex, 
age, race, and baseline weight.
8
Participant Disposition
8.1
Summary of Participant Disposition
Participant disposition will be summarized overall, and by country, and will include the 
number of participants in each analysis set defined in chapter 6, and the number of 
participants in the APTS who

completed the study

withdrew from study
To assess the potential impact of COVID-19 on the visit structure, a table will be provided by 
visit for the visits that are changed from on-site to remote if applicable. The summary will be 
based on APTS.
8.2
Withdrawals
The number of participants who withdrew from study will be summarized by primary reason 
for withdrawal and all reasons for withdrawal.
Participants who withdrew from study will be listed and the listing will include the number of 
days since the first IMP until withdrawal from study, the number of days since the last IMP,
and the primary reason for withdrawal, and all reasons for withdrawal.
Kaplan-Meier failure plots of time to withdrawal from study will be presented. The time will 
be calculated from the date of first dose of IMP to the date of the withdrawal from study or 
the date of the Completion Visit, whichever comes first. Participants who were in the trial
until the Completion Visit or Week 48, whichever comes first, will be regarded as censored
from that timepoint.
All tables, graphs, and listings will be based on the APTS.
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9
Demographics and Baseline Characteristics
Demographics (sex, age, race, region, country); baseline characteristics (height, weight, and 
BMI); baseline disease characteristics; and baseline efficacy variables will be summarized.
Baseline disease characteristics comprise of prior preventive medications used, number of
treatment failures and reasons for treatment failures for all and by prior preventive 
medications. Furthermore, family history of CH (yes/no), relatives with a CH diagnosis, time 
since first symptoms of CH, time since cCH diagnosis, any previous change over time for the 
CH phenotype, time since the beginning of the current period of attacks, duration of the last 
remission period (in weeks), usually have a remission period (yes/ no), length of remission 
period if applicable, ability to predict the start of attacks after a remission period (yes/no), 
seasonal beginning of cCH attack periods (yes/no), season where the cCH attack periods 
begin if applicable, usual duration of CH attack period (in weeks), usual start time of CH 
attacks (hourly intervals/unknown), usual number of CH attacks per day, usual duration of the 
attacks (in minutes), trigger factors (yes/no), which trigger factors if applicable, usual pain 
intensity, and the accompanying symptoms are also considered baseline disease 
characteristics. See Panel 3 for more details regarding the categories.
Panel 3
Categories for baseline disease characteristics
Variable
Categories
Treatment failures
Lack of efficacy, safety/tolerability, contraindication, participant in 
remission period, other
Relatives with a CH diagnosis
Mother, father, sister, brother, mother’s mother, mother’s father, father’s 
mother, father’s father, daughter, son
Change over time for CH phenotype
No, from episodic to chronic, from chronic to episodic back to chronic
Length of remission period
<1 month, 1 month <= and < 2 months, 2 months <= and <= 3 months
Season where cCH attack periods 
begin
Spring, summer, autumn, winter, other
Trigger factors
Alcohol, sleep, stress, other
Usual pain intensity
No pain or barely any pain, mild pain, moderate pain, severe pain, 
excruciating pain
The eDiary reported baseline efficacy variables that will be summarized are the number of 
weekly attacks, number of times abortive medication (triptans and/or oxygen, oxygen, 
triptans) was used weekly, weekly integrated measure of frequency and intensity of attack 
related pain, average attack related daily pain score, and average pain per attack, which are all 
collected during the 28-day Screening Period.
The other baseline efficacy variables that will be summarized are: SIS domain scores, EQ-5D-
5L descriptive items as well as the visual analogue scale (VAS) scores of the overall health 
state, and WPAI:GH2.0 sub-scores.
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Concurrent as well as relevant past medical, neurological, and psychiatric disorders will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) and summarized by 
SOC and preferred term. 
A concurrent medical, neurological, or psychiatric disorder is a disorder that is ongoing at the 
Screening Visit. A past medical, neurological, or psychiatric disorder is a disorder that ended 
prior to the Screening Visit.
Social history will be summarized.
Demographics and baseline characteristics will be summarized based on the APTS, and 
baseline efficacy variables will be summarized based on the FAS.
10 Recent and Concomitant Medication
Recent and concomitant medication will be coded using the WHO Drug Dictionary
(WHO-DD).
Medications will be classified according to the start and stop dates and summarized by 
anatomical therapeutic chemical (ATC) code level 4, and generic drug name. Handling of 
missing or incomplete dates is specified in section 23.4.3.
The following categories will be used:

Prior: Medications with a start or stop date before first IMP infusion,

Concomitant: Medications with a start date at or after the date of first IMP infusion, 
medications with a stop date at or after the date of first IMP infusion, medications with a 
start date before first IMP infusion and with no stop date (being ongoing at the end of the 
trial), and medications where both start and stop date are completely missing
The summaries will be repeated for CH medication (only prior), preventive medication, and 
transitional medication.
Transitional medications will be listed based on the APTS. The listing will include the generic 
drug name, indication, time since the first IMP, the duration, the start and end dates, and 
dosing information. 
All disallowed medications will be listed based on the APTS. The listing will include the 
generic drug name, indication, time since the first IMP, the duration, the start and end dates, 
and dosing information. 
The eDiary reported medications will be handled separately. For further details see section 
13.5.8.
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11 Exposure 
The total number of infusions received, and total number of infusions completed as planned 
will be summarized. 
Furthermore, for each infusion visit, the number of infusions received, completed as planned, 
temporarily interrupted, and lasted longer than 45(+15) minutes, as well as descriptive 
statistics for the duration of infusions and for the duration of the infusions that were 
temporarily or fully interrupted will be summarized.
Participants, who at any point during the trial received a different dose than what was 
planned, will be listed. The listing will include all infusion visits, dates of infusion visits, 
planned dose for the participant and actual dose received for the participant. 
In addition, all infusion data will be listed, i.e. the start and stop time of the infusion and the 
duration of the infusion.
The number of participants with a 1-year exposure (for details see section 23.2.2) will be 
summarized.
The summaries will be based on the APTS.
12 eDiary Compliance  
The number and proportion of participants with eDiary data will be summarized and 
presented by 1-week intervals. The summary will for each week include the number of 
participants in the trial for that week, the number and percentages of participants with data for 
that week, and for weeks with daily registrations the percentages of participants with 4, 5, 6 
and 7 days of data.
A participant will count as being in the trial for a week if (s)he has at least 1 day with eDiary 
data in that week.
The summary will be based on the APES.
13
Efficacy
13.1
General Efficacy Analysis Methodology
All confidence intervals (CIs) will be two-sided 95% CIs.
13.2
Testing Strategy
No formal testing will be done.
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13.3
Analysis Methodology for the Primary Endpoints
There are no primary efficacy endpoints. The primary endpoints are safety endpoints that will 
be described in chapter 14.
13.4
Analysis Methodology for the Key Secondary Endpoints
There are no key secondary efficacy endpoints.
13.5
Analysis Methodology for the Secondary and Exploratory Endpoints
13.5.1
Short-term Efficacy Estimand
The short-term efficacy estimand is the mean change from Baseline in the weekly number of 
attacks (Weeks 1-4) for participants with chronic cluster headache receiving IV infusion of 
eptinezumab 400 mg every 12 weeks, without the use of transitional treatment (GON block 
and oral steroids), and regardless of the use of abortive and preventive medication for cluster 
headache, and infusion interruption or termination before full dose is received.
Clinical Question of Interest
The clinical question of interest is changes in cluster headache symptoms within the first 4 
weeks after infusion with eptinezumab 400 mg.
Attributes of the Short-term Efficacy Estimand
The short-term efficacy estimand has the following attributes:

The treatment condition of interest will be IV infusion of eptinezumab 400 mg every 12 
weeks, with or without the use of abortive and preventive medication for cluster headache

The population of interest will be participants with cCH

The endpoint to be obtained to address the clinical question is change from Baseline in 
the weekly number of attacks (Weeks 1-4)

The intercurrent event use of transitional treatment will be addressed by a hypothetical 
strategy estimating the efficacy, in the hypothetical scenario where no transitional 
treatment is available, while interruption or termination of IMP such that full dose is not 
received will be addressed by a treatment policy strategy 

The population level summary will be the mean change across weeks 1-4
13.5.1.1
Rationale for the Short-term Efficacy Estimand
The number of weekly attacks is considered a good measure of the impact of IV infusion of 
eptinezumab 400 mg every 12 weeks, since it captures an important part of the symptoms for 
cluster headache and therefore change from Baseline in the average number of weekly attacks 
will be used as the endpoint for the efficacy estimand described in details in section 13.5.1.
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Justification of Treatment Condition of Interest
The use of abortive medication (triptans and oxygen) is included in the treatment condition of 
interest because abortive medication is taken after an attack begins to affect that specific 
attack. It is not expected that the use of abortive medication will affect the number of attacks
following an attack where abortive medication was taken. Thus, the use of abortive 
medication is not considered to be an intercurrent event.
The use of preventive medication is included in the treatment condition of interest because
eptinezumab is expected to be used with or without other preventive medication for 
participants suffering from chronic cluster headache. Furthermore, though the use of 
preventive medication could influence the number of attacks, the potential effect is expected 
to be limited in a chronic cluster headache population. Thus, the use of preventive medication 
is not considered to be an intercurrent event.
Intercurrent Events
The following intercurrent events, occurring after treatment initiation and potentially affecting 
either the interpretation or the existence of the measurements associated with the clinical 
question of interest, are considered.
Use of transitional treatment (GON block and oral steroids) – hypothetical strategy
Use of transitional treatment could change the disease status considerably, and thus 
influence the number of attacks. In a study, 35% of the participants taking the oral 
steroid prednisone experienced a complete cessation of cluster headache attacks after 7 
days compared to 7% in the placebo group and 49% taking prednisone experience at 
least a 50% reduction of cluster headache attacks compared to 15% for the placebo 
group after 7 days.1 To get a clearer picture of the change in symptoms after infusion 
with eptinezumab, a hypothetical strategy has been chosen to address this, estimating 
the effect if no transitional treatment was available, using the 7 day limit1 as described 
in section 23.2.1.5. Due to the expected positive effect of transitional treatment this is 
considered a conservative approach.
Interruption or termination of IMP such that full dose is not received – treatment policy 
strategy
If an IMP is stopped prematurely (either temporarily or completely) the consequence 
is that the participant did not receive all of the intended dose of eptinezumab and it 
could be expected that the potential effect of eptinezumab could be decreased due to 
the lower dose. To be conservative, a treatment policy strategy is used to address this.
13.5.1.1.1
Missing Data
Details of imputation of missing data are provided in section 23.2.1.3.
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13.5.1.2
Estimator
To estimate the change from Baseline in the number of weekly attacks (Weeks 1-4) described 
above, a Mixed Model for Repeated Measurements (MMRM) using a restricted maximum 
likelihood (REML)-based approach will be used. The data used for the MMRM is FAS and 
DPS2. The MMRM will include the following fixed effects: week (1, 2, 3, 4, 13, 14, 15, 16, 
25, 26, 27, 28, 37, 38, 39, 40), and country (for details see section 23.2.3) as factors, 
logarithm of the baseline score as a continuous covariate, and the logarithm of the baseline 
score-by-week interaction. An unstructured covariance structure will be used to model the 
within-participant errors. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. The change from Baseline in the number of weekly attacks 
(Weeks 1-4) will be estimated as the average from the least squares estimates from the 
MMRM for the week effect using the contrast [1, 1] [1, 2] [1, 3] [1, 4] /divisor = 4. The 
SAS® code for the analysis is shown in Appendix II. If this analysis fails to converge the 
following covariance structures will be tried out:

UN(15) - banded unstructured

UN(14) - banded unstructured

UN(13) - banded unstructured

UN(12) - banded unstructured

TOEPH – heterogenous Toeplitz 

CSH – heterogenous compound symmetry

TOEP - Toeplitz

CS - Compound Symmetry  
and the one with the lowest AIC amongst the ones that converged will be applied. In case of 
no models converging, the results will only be shown as described in chapter 7.
13.5.2
Additional Short-term Efficacy Estimand
In addition to the short-term efficacy estimand described in section 13.5.1 the population level 
summary ‘mean change across weeks 1-2’ will be considered with everything else as 
described in section 13.5.1 except that the contrast used is [1, 1] [1, 2] /divisor = 2. 
13.5.3
Long-term Efficacy Estimand
The long-term efficacy estimand is the mean change from Baseline in the monthly number of 
attacks (Months 1-12) for participants with chronic cluster headache receiving IV infusion of 
eptinezumab 400 mg every 12 weeks, without the use of transitional treatment (GON block 
and oral steroids), and with continuation of treatment eptinezumab 400 mg for 12 months, and 
regardless of use of abortive and preventive medication for cluster headache, and infusion 
interruption or termination before full dose is received.
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The approach described in section 13.5.1 also apply for the long-term estimand with a few 
adjustments:

The clinical question of interest is changes in cluster headache attacks within the 12 
months after infusion with eptinezumab 400 mg. 

The endpoint to be obtained to address the clinical question is change from Baseline in 
the monthly number of attacks (Months 1-12)

The population level summary will be the mean change across Months 1-12

The intercurrent events use of transitional treatment and interruption or termination of 
IMP such that full dose is not received will be handled as in section 13.5.1. Furthermore, 
when the primary reason is either “Lack of Efficacy” or “Adverse Events” for withdrawal 
from treatment this will be considered an intercurrent event that will be handled by a 
hypothetical strategy
Intercurrent Events
In addition to the intercurrent events described above, the following intercurrent event, 
occurring after treatment initiation and potentially affecting either the interpretation or the 
existence of the measurements associated with the clinical question of interest, is considered.
Withdrawal from treatment due to “Lack of Efficacy” or “Adverse events” –
Hypothetical strategy
For participants withdrawing from treatment, the majority of the effect is expected to be seen 
within the first 12 weeks following their last infusion and therefore data that occur beyond 12 
weeks after their last infusion will not be considered.
Estimator
The intercurrent event withdrawal from treatment will be handled by a hypothetical strategy 
estimating the effect where all participants continue their treatment with eptinezumab 400 mg 
for 12 months by not including data collected 3 months or more after the latest infusion.
Furthermore, the following adjustments are needed compared to the estimator in section 
13.5.1

The week variable in the MMRM will be replaced by Month 1 to 12

The DPS2 will be replaced by DPS3

The contrast that will be used is given as [1, 1] [1, 2] [1, 3] [1, 4] [1, 5] [1, 6] [1, 7] [1, 8] 
[1, 9] [1, 10] [1, 11] [1, 12] /divisor = 12
13.5.4
Rationale for the Efficacy Endpoints following the strategy of the Long-term 
Efficacy Estimand
Regarding the efficacy endpoints based on the number of cluster headache attacks, intensity
of pain or use of abortive medication, the data handling will follow the strategies described in 
section 13.5.3. For all of these endpoints, the intercurrent events use of transitional treatment 
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and interruption or termination of IMP such that full dose is not received and withdrawal from 
treatment will be handled as described in section 13.5.3.
For endpoints based on the number of attacks the rationale is the same as previously 
described. For endpoints based on intensity of pain the same strategies are used since not 
getting the full dose (by interruption/termination of IMP or withdrawal from treatment) is 
expected to also affect the pain as well as use of transitional treatment is expected to decrease 
the pain severity.1 For endpoints based on the use of abortive medication, not getting the full 
dose (by interruption/termination of IMP or withdrawal from treatment) is expected to also 
affect the use of abortive medication. Furthermore, the use of transitional treatment is 
expected to reduce the number of attacks and therefore is also expected to reduce the number 
of times abortive medication can be used.
13.5.5
Intercurrent Events and Withdrawal from Treatment
The number of participants who experienced the intercurrent event “use of transitional 
treatment” and “interruption or termination of IMP such that full dose is not received” during 
Weeks 1-4 will be summarized for the short-term efficacy estimand defined in sections 13.5.1
and 13.5.2.
The number of participants who experienced the intercurrent events “use of transitional 
treatment”, “interruption or termination of IMP such that full dose is not received” and 
“withdrawal from treatment” during Months 1-12 will be summarized for the long-term
efficacy estimand following the definition in section 13.5.3.
The number of participants who withdrew from treatment will be summarized by primary 
reason for withdrawal and all reasons for withdrawal.
Participants who withdrew from treatment will be listed and the listing will include the 
number of days in the trial until withdrawal from treatment, the number of days since the last
IMP, and the primary reason for withdrawal, and all reasons for withdrawal.
13.5.6
Efficacy Analysis
13.5.6.1
Continuous Efficacy Endpoints
In the eDiary, information regarding number of attacks, level of severity of pain of the 
attack(s) as well as use of abortive medication is gathered daily or weekly. When analysing 
data from the eDiary, three different data structures will be considered: weekly scores based 
on daily data, monthly scores based on weekly scores (regardless of the weekly scores 
originating from data being daily or weekly), and weekly scores based on either daily or 
weekly reported data covering all weeks which will be used descriptively to show the data 
over time (for further details see section 23.1). The endpoints listed below are covered by 
applying the three different data structures in the MMRM as in section 13.5.1.2 using FAS 
and DPS3 with the relevant time variable, appropriate baseline value (for endpoints 
considering weekly/monthly attacks and integrated measure the log-transformed baseline 
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values will be used for all other endpoints there will be no transformation of the baseline 
values), and the appropriate contrast statement as well as a different list of covariance 
structures to get estimates of mean values, their standard errors (SEs) as well as two-sided 
95% CIs:

Change from Baseline in the weekly number of times an abortive therapy (oxygen and/or 
triptans) was used (Weeks 1-4, 13-16, 25-28, 37-40)

Change from Baseline in the number of weekly attacks (Weeks 1-4, 13-16, 25-28, 37-40)

Change from Baseline in the average attack related daily pain (including days with no 
attacks), as assessed using the 5-point self-rating pain severity scale (Weeks 1, 2, 3, 4, 13, 
14, 15, 16, 25, 26, 27, 28, 37, 38, 39, 40)

Change from Baseline in the number of monthly attacks (Months 1,2, …, 12)

Change from Baseline in the pain per attack assessed by the 5-point self-rating pain 
severity scale scores (Months 1,2, …, 12)

Change from Baseline in the monthly number of times an abortive therapy (oxygen and/or 
triptans) was used (Months 1,2, …, 12)

Change from Baseline in the weekly integrated measure of frequency and intensity of 
attack related pain, that is, the sum of the intensity (worst pain on a 5-point self-rating pain 
severity scale) for each attack during a week (Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 27, 
28, 37, 38, 39, 40) or the intensity of attack related pain multiplied by the weekly number 
of attacks (Weeks 5, 6, …, 12, 17, 18, …, 24, 29, 30, …, 36, 41, 42, …, 48)
Continuous endpoints using weekly scores based on daily data will first use an unstructured 
covariance structure. If this analysis fails to converge the following covariance structures will 
be tried out:

UN(15) - banded unstructured

UN(14) - banded unstructured

UN(13) - banded unstructured

UN(12) - banded unstructured

TOEPH – heterogenous Toeplitz 

CSH – heterogenous compound symmetry

TOEP - Toeplitz

CS - Compound Symmetry  
and the one with the lowest AIC amongst the ones that converged will be applied.
Continuous endpoints using monthly scores will first use an unstructured covariance structure. 
If this analysis fails to converge the following covariance structures will be tried out:

UN(11) - banded unstructured

UN(10) - banded unstructured

UN(9) - banded unstructured

TOEPH – heterogenous Toeplitz 

CSH – heterogenous compound symmetry

TOEP - Toeplitz
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
CS - Compound Symmetry  
and the one with the lowest AIC amongst the ones that converged will be applied.
Weekly scores based on daily or weekly reported data will try out the following list of 
covariance structures:

CSH – heterogenous compound symmetry

TOEP - Toeplitz

CS - Compound Symmetry  
and the one with the lowest AIC amongst the ones that converged will be applied.
In addition to estimates, SEs and CIs the following estimates will be calculated:

Change from Baseline in the number of weekly attacks, the weekly pain per attack score,
the average attack related daily pain, the weekly integrated measure of frequency and 
intensity of attack related pain, and the weekly number of times an abortive therapy was 
used for Weeks 1-2 and Weeks 1-4 using data type 1)

Change from Baseline in the number of monthly attacks, the monthly pain per attack score, 
the monthly integrated measure of frequency and intensity of attack related pain, and the 
monthly number of times an abortive therapy was used for Months 1-3, Months 4-6, 
Months 7-9, Months 10-12, Months 1-6, Months 7-12 and Months 1-12 using data type 2) 
Each SIS domain score, the EQ-5D-5L VAS and each WPAI:GH2.0 sub-score will be 
analysed using the MMRM from section 13.5.1.2 considering FAS with the relevant time 
variable and appropriate baseline value (not log-transformed) as well as the same approach for 
choice of covariance structure to be applied. 
PGIC will be analysed using the MMRM from section 13.5.1.2 considering FAS with the 
relevant time variable and no baseline value as well as the same approach for choice of
covariance structure to be applied. 
13.5.6.2
Efficacy Endpoints Regarding Response
For endpoints regarding response (30%, 50%, 75% or 100%) or sustained response (75%), the 
number and percentage of responders using weekly number of attacks for Week 1, Week 2, 
Week 3, Week 4, Week 5, …., Week 48 and the number and percentage of responders using 
monthly number of attacks for Month 1, Month 2, …, Month 12 will be presented without 
imputations other than described in section 13.5.1.1.1. Additionally, sensitivity analyses will 
be made using LOCF and worst case imputations, for further details see section 13.5.9.3. For 
all of these analyses DPS3 will be used when determining whether a participant is a responder 
or not.
Furthermore, the number and percentage of responders will be found for the following periods 
of time (for details see section 23.2.1.7):

Months 1–3, Months 4-6, Months 7-9, Months 10-12

Months 1-6, Months 7-12
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
Months 1-12
13.5.6.3
Other Efficacy Endpoints
Endpoints that are not covered by sections 13.5.6.1 and 13.5.6.2 will only be summarized 
descriptively as described in chapter 7. 
13.5.6.4
Subgroup Analyses
The subgroups to be investigated are participants who are treatment resistant and participants 
who are not (see section 23.2.5 for a definition of treatment resistant). The endpoint to be 
considered for these subgroup analyses is Change from Baseline in the number of monthly 
attacks (Months 1,2, …, 12). 
13.5.7
Rationale for Selected Analysis Method for the Secondary and Exploratory 
Endpoints
The MMRM model is chosen as it is a very flexible and robust analysis, and with the selected 
explanatory variables it will allow the endpoint to vary freely by visit, account for the baseline 
level and for country differences, and it includes the most flexible structure for within 
participant variation. This will allow the use of all participants also those who withdraw or 
have missing data.
13.5.8
eDiary Reported Use of Medication
In the headache eDiary, participants are asked each day or each week (depending on whether 
a participant is in a period with daily or weekly registrations) to fill out whether they used any 
of the following medications during that day/week: oxygen, triptans, or other. The number
and percentage of participants taking each of the medication types will be presented for each 
4-week interval in the trial including baseline values.
13.5.9
Sensitivity Analyses of Secondary and Exploratory Endpoints
13.5.9.1
Sensitivity Analyses to assess the impact of the use of transitional medication
To assess the impact of the use of transitional treatments, the MMRMs described in sections
13.5.1 and 13.5.3 will be used to analyse data where all data are included also immediately 
after receiving a transitional treatment corresponding to a treatment strategy. It will only be 
done for the endpoints described in sections 13.5.1 and 13.5.3 respectively.
13.5.9.2
Sensitivity Analyses to assess the impact of the strategy of handling 
withdrawal from treatment
To assess the impact of the chosen hypothetical strategy for handling withdrawal from 
treatment the MMRM described in section 13.5.3 will be used to analyse data where all data 
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are included corresponding to a treatment strategy. It will only be done for the endpoint 
described in section 13.5.3.
13.5.9.3
Sensitivity Analyses to assess the impact of missing data regarding response
To assess the impact of only imputing data by prorating for response endpoints as described 
in section 13.5.6.2, LOCF and worst case imputations will be carried out for the endpoints 
regarding 75% response.
14 Safety
14.1
Adverse Events
14.1.1
General Methodology for Adverse Events
Unless otherwise specified, tables, graphs, and listings will be based on the APTS.
Tables by preferred term and tables by system organ class (SOC) and preferred term will be 
sorted in descending order based on the percentages of participants with these adverse events.
Unless otherwise specified, the summaries of adverse events will include the number and 
percentage of participants with an adverse event, and the total number of events. In tables 
displaying SOC or preferred terms, participants are counted only once within each SOC or 
preferred term.
Listings of adverse events will be sorted by site, treatment group, participant screening 
number, and adverse event start date, and include preferred term, investigator term, adverse 
event start date, the date of first IMP infusion, the date and time of the latest IMP infusion 
prior to the adverse event, the time since latest IMP infusion, duration of the adverse event, 
action taken, causality, intensity, seriousness, and outcome. Furthermore, sex, age, race and
baseline weight will be presented if available. For adverse events that change in intensity, 
each intensity will be included. In listings of adverse events, start or stop dates will be 
displayed as collected also in case of partially or completely missing dates. 
14.1.2
Coding of Adverse Events
Adverse events will be coded using MedDRA, Version 25.0 or later.
14.1.3
Classification of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:

pre-treatment adverse event – an adverse event that starts on or after the date the 
participant signed the Informed Consent Form(s) and prior to the date and time of first 
dose of eptinezumab
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
treatment-emergent adverse event (TEAE) – an adverse event that starts during or after 
administration of the first dose of IMP, or a pre-treatment adverse event that increases in 
severity or becomes serious during or after administration of the first dose of IMP
For handling of adverse events with incomplete start dates to facilitate this classification, see 
section 23.4.4. Note that adverse events with incomplete start dates will be classified as not 
being treatment-emergent if the causality to IMP is “Not Related - Prior to IMP”.
An adverse event is considered causally related to the use of eptinezumab when the causality 
assessment by the investigator is probable or possible. If the causality assessment is missing,
the adverse event is considered causally related.
14.1.4
Presentation of Adverse Events
All adverse events will be listed for the APES, including a flag for TEAEs.
The numbers, and percentages of participants with TEAEs, TEAEs leading to infusion 
interruption, serious adverse events (SAEs), or adverse events leading to withdrawal, and of 
participants who died will be presented based on the APTS.
14.1.5
Presentation of Treatment-emergent Adverse Events
The following summaries will be provided:

TEAEs by SOC and preferred term

TEAEs by preferred term

TEAEs by sex and preferred term

TEAEs with an incidence ≥2% by preferred term

causally related TEAEs by SOC and preferred term

TEAEs by intensity (mild/moderate/severe), SOC, and preferred term

causally related TEAEs by intensity, SOC, and preferred term

TEAEs occurring on the day of dosing after infusion start by SOC and preferred term (this 
includes the days of the first, second, third and fourth infusion)

TEAEs by infusion Periods by SOC and preferred term (this includes time between the 
start of the first and second infusions, second and third infusions, third and fourth 
infusions, and within 12 weeks after the start of the fourth infusion)
14.1.6
Presentation of Deaths
All the adverse events in participants who died will be listed for the APES.
14.1.7
Presentation of Serious Adverse Events
All the SAEs will be listed for the APES.
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Treatment-emergent SAEs will be summarized based on APTS by:

SOC and preferred term

preferred term
14.1.8
Presentation of Adverse Events Leading to Withdrawal
All the AEs leading to withdrawal will be listed for the APES.
TEAEs leading to withdrawal will be summarized by:

SOC and preferred term

preferred term
14.1.9
Presentation of Adverse Events leading to Trial Drug Infusion Interruption or 
Termination
All AEs leading to trial drug infusion interruption or termination will be listed for the APES. 
TEAEs leading to trial drug infusion interruption or termination will be summarized based on 
APTS by:

SOC and preferred term
14.1.10 Presentation of Adverse Events of Special Interest
Treatment-emergent adverse events of special interest (AESI) will consist of the preferred 
terms defined by the SMQs/HLTs/HLGTs listed in Table 5.
The following summaries of treatment-emergent AESIs will be provided:

AESIs by SOC and preferred term

AESIs by SOC and preferred term, separately for each individual event category 
The summaries will be provided for the APTS.
14.2
General Methodology for Other Safety Data
Unless otherwise specified, tables, graphs, and listings will be based on the APTS.
The denominators for the summaries of a given variable will be based on the number of 
participants with non-missing values at a given visit or during the assessment period.
Descriptive statistics for the safety variables, both absolute values and changes from Baseline, 
will be presented by visit.
The number and percentage of participants with at least one PCS value at any post-baseline 
assessment time point will be summarized by variable. All available assessments will be 
included in the evaluation of PCS values. 
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For participants with post-baseline PCS values, listings will be provided including all the 
values for those participants for the variable, with flagging of PCS values and out-of-
reference-range values.
All the adverse events in participants with post-baseline PCS values will be listed by
participant screening number; the listing will include the PCS value, the assessment date, the 
change from Baseline in PCS value, the preferred term for the adverse event, and start date
and stop date of the adverse event. The PCS values and adverse events will be listed in 
chronological order according to assessment date and the start date of the adverse event.
14.3
Clinical Safety Laboratory Test Data
14.3.1
Data Presentation
The PCS criteria used for the clinical safety laboratory are the Lundbeck standard PCS criteria 
described in SOP_09978: GPV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studies, version 6, and are also included in
Table 2.  
The clinical safety laboratory test values will be presented in both conventional and Système 
International (SI) units.
Fasting lipid and fasting glucose concentrations will be presented in separate tables from the 
overall laboratory tables.
For urine dipsticks, for which the results are categorical values (for example, negative, trace, 
1+, 2+), the number and percentage of participants will be summarized by visit for each test.
The microscopy results will be listed by assessment time point for participants with findings.
14.3.2
Potential Drug-induced Liver Injury (DILI)
Signals of DILI will be assessed according to the FDA guideline2 using the following criteria:

ALT or AST >2×, >3×, >5×, >10×, or >20×ULN

total bilirubin >2×ULN

alkaline phosphatase >1.5×ULN

ALT or AST >3×ULN AND total bilirubin >1.5× or >2×ULN
Participants fulfilling any of the criteria will be listed, and the listing will include all the ALT, 
AST, bilirubin, and alkaline phosphatase values for those participants, sorted by assessment 
date and time in ascending order. If a criterion for a test is fulfilled, the value will be flagged 
with the highest criterion fulfilled (for example, AST >3×ULN, >5×ULN, >10×ULN, or 
>20×ULN).
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In addition, assessment time points for participants for whom Hy’s Law is potentially fulfilled 
will also be flagged in the listing (pHYL):

ALT or AST >3×ULN AND

alkaline phosphatase <2×ULN AND

total bilirubin ≥2×ULN
The number of participants who met any of the criteria specified above at any post-baseline 
visit will be summarized. In the summaries, each participant will be counted only once using 
the maximum assessment, or the most severe for the combined criteria. The summaries will 
also include the number of potential Hy’s Law cases. 
14.4
Vital Signs and Weight
The PCS criteria used for vital signs and weight are the Lundbeck standard PCS criteria 
described in SOP_09978: GPV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studies, version 6, and are also included in
Table 2.
Descriptive statistics for the vital signs, weight, and BMI, both absolute values and changes 
from Baseline, will be presented by visit. The number of participants exceeding the PCS 
values will be tabulated.
14.5
ECGs
The PCS criteria used for the ECG parameters are the Lundbeck standard PCS criteria 
described in SOP_09978: GPV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studies, version 6, and are also included in
Table 3. 
In addition to the tables and listings specified in section 14.2, absolute values and changes 
from Baseline in QTcF will also be summarized categorically by visit. The categories that will 
be used are as follows for the absolute QTcF values:

QTcF interval < 450 msec

QTcF interval 450 - 480 msec

QTcF interval > 480 - 500 msec

QTcF interval > 500 msec
The categories that will be used for the change from Baseline QTcF values are:

QTcF interval increase from baseline > 30 msec

QTcF interval increase from baseline > 60 msec
Furthermore, the number and percentage of participants being classified as having either a 
normal, abnormal but not clinically significant, abnormal and clinically significant, or not 
interpretable ECG result based on the overall interpretation of the ECG from the investigator 
will be summarized by visit.   
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14.6
Other Safety Endpoints
14.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores
The C-SSRS was administered:

for lifetime (using the Baseline/Screening Version) – the C-SSRS assessment at screening 
that collects a lifetime recall

for the past 1 month at screening (using the Baseline/Screening Version) – the C-SSRS 
assessment at screening that focuses on the last month

at Baseline (using the Since Last Visit Version) – the C-SSRS assessment at Baseline that 
collects information since the previous visit, for example, from screening to Baseline

post-baseline (using the Since Last Visit Version) – the C-SSRS assessments after Baseline
The numbers and percentages of participants with lifetime, past 1 month, baseline, or post-
baseline suicide-related events based on the C-SSRS will be summarized. For each summary, 
the most severe item with an answer “Yes” for each participant according to the ordering 
given in Panel 4 is displayed. For the post-baseline assessments, the most severe score (Panel 
4) per participants related to suicidal ideation and/or behaviour will be summarized.  
The number and percentage of participants with no suicidal ideation or behaviour will be 
summarized. 
Panel 4
C-SSRS Scores
C-SSRS Score
Related to:
1
Wish to be dead
Suicidal ideation
2
Non-specific active suicidal thoughts
3
Active suicidal ideation with any methods (not plan) without intent to act
4
Active suicidal ideation with some intent to act, without specific plan
5
Active suicidal ideation with specific plan and intent
6
Preparatory acts or behaviour
Suicidal behaviour
7
Aborted attempt
8
Interrupted attempt
9
Non-fatal suicide attempt
10
Completed suicide (only applicable for the post-baseline assessments)
The C-SSRS scores will be summarized based on the APTS for participants with at least one 
post-baseline C-SSRS assessment, regardless of whether they had a baseline C-SSRS 
assessment.
Missing C-SSRS scores will not be imputed.
Positive responses to non-suicidal self-injurious behaviour will be summarized separately.
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For participants with any post-baseline suicidal ideation or behaviour (C-SSRS scores of 1 to 
10), listings will be provided including all C-SSRS scores for those participants.
15 Immunogenicity
For participants with pre-existing antibodies at Baseline, the number and percent of 
participants who are positive for anti-eptinezumab antibody will be summarized. In addition, 
for each scheduled visit and for the entire trial the number and percent of participants who are 
positive for anti-eptinezumab will be summarized. Denominators for percentages will be the 
number of participants with a sample taken for the specified visit. For participants with ADA, 
neutralizing properties of anti-eptinezumab antibodies will also be summarized. Participants 
with at least one visit with a positive ADA result (the confirmatory test being positive) will be 
considered as an ADA positive participant. Participants with no positive ADA results will be 
considered as ADA negative participants.
Participants’ titer per visit and peak positive titer showing median, min, max and IQR for the 
peak values will be summarized.
Participants with first positive ADA result at the different visits and how many out of these 
had all the following results also being positive will be summarized. If missing values occur 
after a positive result this will also count as a following result being positive.
Participants with a positive anti-eptinezumab antibody result will be listed. The listing will 
include visit, sampling assessment date, final ADA result, titre result and final Nab result.
In addition, summaries of TEAEs by SOC and preferred term will be provided for participants
who are ADA-positive as well as ADA-negative. Furthermore, summaries of TEAEs of 
Hypersensitivity and Anaphylactic Reactions by SOC and preferred term will be provided for 
participants who are ADA-positive as well as ADA-negative.
Furthermore, adverse events in participants with positive anti-eptinezumab antibody results or 
with pre-existing antibodies at Baseline will be provided. The listing will include the
preferred term for the adverse event and start date and stop date of the adverse event.
16 Biomarker
The results from the analyses described in this section will be presented in an addendum to 
the clinical trial report.
The biomarker that will be presented is CGRP covered by the exploratory endpoint “Change 
from Baseline in CGRP (CGRP-eptinezumab complex, free CGRP) (Week 0 after IMP 
infusion, and Weeks 12, 24, 36, and 48)” and will be considered for the values measured prior 
to an IMP infusion as well as the values after an IMP infusion.
The baseline values of CGRP-eptinezumab complex and free CGRP will be summarized.
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Numbers, arithmetic mean, standard deviation, median, lower and upper quartiles, minimum 
and maximum values as well as the percentage change from Baseline will be summarized by 
Visits before and after an IMP infusion for Weeks 12, 24 and 36 and once for Week 48.
The baseline value will be the value measured before the beginning of the first IMP infusion 
at the Baseline Visit.
For all other visits the acceptable ranges for measurements are defined as a value measured on 
the same date as an IMP infusion but prior to the IMP infusion being started is the 
measurement to be used as the prior value. A measurement made 55 minutes after the IMP 
infusion ended and the rest of that day will be assigned as the after IMP value.
17 Pharmacokinetic/Pharmacodynamic Analyses
A PK/PD analysis will be planned and conducted by PKPD modelling & simulation,
H. Lundbeck A/S, and reported separately.
18 Data Reviews
The quality of the trial will be overseen by performing data reviews during the conduct of the 
trial. The reviews may include, but are not limited to, data quality, protocol adherence, and 
the appropriateness of design assumptions, including the sample size assumptions. 
19 Interim Analyses
No interim analysis is planned.
20 Sample Size Considerations
In line with the ICH E1 guideline,3 the trial aims at providing data in 100 participants exposed 
to eptinezumab for 1 year. Dodick (2020),4 participants 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 NCT02964338,5 in participants 
suffering from cCH, approximately 7% of participants 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 trial is unknown, 
125 participants are planned to be enrolled and treated, allowing for 100 participants to 
complete, with a withdrawal rate of 20%. The withdrawal rate will be monitored during the 
trial conduct, and if a clear deviation from the assumed withdrawal rate is observed, the 
number of participants enrolled and treated might be increased to ensure that data is available 
for a sufficient number of participants with long-term exposure.
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21 Statistical Software
The statistical software used will be SAS®, Version 9.4 or later.
22 Changes to Analyses Specified in the Protocol
In the definition of FAS monthly has been changed to weekly to accommodate that there are 
endpoints considering weekly data.
There has been a clarification of the phrasing of the endpoints from the protocol. Furthermore, 
the names of the different types of endpoints have also been changed to describe these in a 
concise way.
The following endpoints have been added for completeness:

Response: ≥75% reduction from Baseline in the number of weekly attacks (Weeks 1-4, 13-
16, 25-28, 37-40)

Change from Baseline in the weekly integrated measure of frequency and intensity of pain, 
that is, the sum of the intensity (worst pain on a 5-point self-rating pain severity scale) for 
each attack during a week (Weeks 1, 2, 3, 4, 13, 14, 15, 16, 25, 26, 27, 28, 37, 38, 39, 40) 
or the intensity of pain multiplied by the weekly number of attacks (Weeks 5, 6, …, 12, 17, 
18, …, 24, 29, 30, …, 36, 41, 42, …, 48)

Use of triptans (Weeks 1-48)

Use of oxygen (Weeks 1-48)

Use of preventive medication (Weeks 1-48)

Response: ≥75% reduction from Baseline in the number of monthly attacks (Months 1,2, 
…, 12)

Sustained response: ≥75% reduction from Baseline in the number of monthly attacks for 
any month, where all the subsequent Months also had ≥75% reduction from Baseline in the 
number of monthly attacks (Month 1,2, …, 12)

A maximum score of mild in the 5-point self-rating pain severity scale (Months 1, 2, …, 
12)

Change from Baseline in the number of weekly attacks (Weeks 1-4 and Weeks 1-2)

Change from Baseline in the number of monthly attacks (Months 1-12)
The estimand part of the efficacy analyses were not included in the protocol. It has been 
added to the SAP for clarification.
The baseline score is log-transformed for MMRMs using number of weekly attacks, number 
of monthly attacks and weekly integrated measure of frequency and intensity of attack related 
pain.
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23 Details on Data Handling
23.1
Data Structure
Information used for the efficacy analyses is either coming from the eDiary or from visits 
(both site visits and phone contacts). The structure of data depends on the source (eDiary or 
visit) and will be handled differently.
Because of the structure in the eDiary, all information is collected at a daily basis or at a 
weekly basis. This gives the possibility to look at data in three different ways:
1.
Using the first 4 weeks after each IMP infusion providing 16 weekly scores (Weeks 1, 2, 
3, 4, 13, 14, 15, 16, 25, 26, 27, 28, 37, 38, 39 and 40)
2.
Using the 12 monthly scores for the entire trial (Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 
12)   
3.
Using the 48 weekly scores for the entire trial (Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 
13, …., 45, 46, 47 and 48)
The rationale for considering these different ways of using data is:
1.
The first four weeks after each IMP infusion are the periods with the most precise 
information (the participants complete the eDiary on a daily basis) and more likely it will 
be possible to use the most appropriate covariance structure
2.
The months use as much information as possible since monthly scores are imputed across 
4 weeks
3.
All weeks show in more detail the development across time during the entire trial with a 
limitation in the choice of variance structure
Thus, if numbers (estimates) can be found from MMRMs using more than one of the above 
data structures the order of preference is if the data structure in 1) is applicable for finding the 
number of interest use this, if 1) is not appropriate and 2) is appropriate use 2), if neither 1) or 
2) is appropriate then use 3). More specifically, for endpoints considering Weeks 1-4, 13-16, 
25-28, 37-40 the results from 1) will be the most valid, for endpoints considering Months 1,2, 
…, 12 the results from 2) will be the most valid, and for endpoints considering Weeks 1, 2, 
…, 48 the results from 3) will be the most valid. The endpoints considering intervals across 
Weeks 1 to 48:

Conversion from cCH to episodic cluster headache (eCH): no cluster headache attacks for 
≥3 consecutive months (≥12 consecutive weeks) (Weeks 1-48)

cCH remission: no cluster headache attacks for ≥1 month (≥4 consecutive weeks) (Weeks 
1-48)

cCH remission: no cluster headache attacks for ≥1 month (≥4 consecutive weeks) (Weeks 
1-12, 13-24, 25-36, 37-48)

Use of transitional treatment (Weeks 1-48)

Use of triptans (Weeks 1-48)

Use of oxygen (Weeks 1-48)

Use of preventive medication (Weeks 1-48)
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do not fit into either of the data structures in 1), 2) or 3) but will be assessed by a yes if the 
participant is fulfilling the criteria in the endpoint. 
The ePRO data measured in connection with visits will be looked at in one way: the relevant 
week numbers corresponding to the visits will be considered in the analyses.
23.2
Derived Variables
23.2.1
eDiary
23.2.1.1
The 5-point Self-rated Pain Severity Scale Scores
The 5-point self-rated pain severity scale scores are used for several endpoints expressing the 
intensity of pain in different ways using distinct formulas. Common for them all is, that if the 
number of cluster headache attacks is reported to be 0, the corresponding pain will be set to be 
the category expressing no pain (no pain/barely any pain) since a participant will not be asked 
to rate the pain when 0 attacks are reported. The scores used in the analyses will be 0 (no 
pain/barely any pain) to 4 (excruciating pain).
23.2.1.2
Calculation of Baseline eDiary Assessments
Calculation of the eDiary baseline begins on the day of the Screening Visit.
In case of a 7-day extension of the Screening Period the last 21 days of the original 28 days 
Screening Period and the first 7 days of the extension will be used to calculate the baseline 
value. In case the extension is less than 7 days more days will be used from the Screening 
Period ending up with a total of 28 days.
When finding the baseline value for number of monthly attacks, the number of reported 
attacks will be scaled up to 28 days using (assuming that days with missing data are similar to 
the days with data):
28*(Reported number of attacks/Reported eDiary Days)
The average weekly number of attacks at baseline will be found by dividing the number of 
monthly attacks at baseline by 4:
28*(Reported number of attacks/Reported eDiary Days)/4
When finding the baseline number of times abortive medication was used the above formulas 
are used with Reported number of attacks replaced by Reported number of times an abortive 
medication was taken.
When finding the baseline values using the 5-point self-rated pain severity scale scores, three 
different formulas will be used. The baseline monthly pain per attack is found by:
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Sum of reported pain across attacks/Number of reported attacks
The baseline weekly pain per attack equals the baseline monthly pain per attack.
The baseline average attack related daily pain is found by:
Sum of the average daily pain across days with data/Number of days with data
where days with 0 attacks will add a value of 0 to the nominator and count as a day in the 
denominator.
The baseline monthly integrated measure of frequency and intensity of attack related 
pain is found by:
((Sum of reported pain across days with data/Number of days with data)*28)/4
where days with 0 attacks will add a value of 0 to the nominator and count as a day in the 
denominator.
The baseline weekly integrated measure of frequency and intensity of attack related pain
equals the baseline monthly integrated measure of pain.
23.2.1.3
Imputation of Missing Post-baseline eDiary Assessments
The strategy of imputation of missing values is given by:
1.
For each weekly score in the periods with daily entries in the eDiary, prorating is used to 
impute any missing data when data have been observed for at least 4 days in a week, to 
have full weekly scores
2.
For each monthly score, prorating is used to impute any missing data when data have 
been observed for at least 2 weeks in a month (after prorating weekly scores), to have full 
monthly scores
For a 7-day weekly period where the eDiary is completed in at least 4 out of 7 days, the 
number of attacks will be calculated using prorating:
7*(Reported number of daily attacks/Reported eDiary Days)
For participants where the eDiary is completed in 3 days or less, the 7-day weekly observation 
will be set to missing.
For a 4-week monthly period where the eDiary is completed in at least 2 out of 4 weeks, the 
number of attacks will be calculated using prorating:
4*(Number of weekly attacks/Reported eDiary Weeks)
For participants where the eDiary is completed in 1 week or less the 4-week monthly 
observation will be set to missing.
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Use of abortive medication is prorated using the same criteria and formulas as above where 
Reported number of daily attacks is replaced by Reported number of daily times an abortive 
medication was taken and Number of weekly attacks is replaced by Number of weekly times 
an abortive medication was taken.
The severity of attacks is prorated using the same criteria as above using the same formulas as 
in section 23.2.1.2.
The derivation of the three pain scores can be seen in Panel 5. When calculating the average 
attack related daily pain and the weekly integrated measure of frequency and intensity of 
attack related pain, a value of 0 will be added to the nominator and count as a day in the 
denominator for days/weeks with 0 attacks. Furthermore, the weekly pain per attack is not 
defined for days/weeks with 0 attacks.
Panel 5
Definitions of Post-Baseline Pain Scores
Daily eDiary
Weekly eDiary
Average attack related daily 
pain
Sum of the average daily pain across 
days with data/number of days with 
data
NA
Weekly pain per attack
Sum of pain across attacks/number of 
attacks
Pain
Monthly pain per attack 
Sum of the weekly pain per attack scores/ number of the weekly pain per 
attack scores
Weekly integrated measure of 
frequency and intensity of 
attack related pain
(Sum of pain across days with data 
/days with data)*7
Pain*number of attacks
Monthly integrated measure of 
frequency and intensity of 
attack related pain
Sum of the weekly integrated measure of frequency and intensity of attack 
related pain scores/ number of the weekly integrated measure of frequency 
and intensity of attack related pain scores
23.2.1.4
Assigning Week to eDiary Assessments
The day of an infusion starts a new week e.g. the day of the first infusion is the first day of
Week 1.
Weekly assessments coming from the eDiary will be assigned to a week using the day of an 
infusion as a starting point. Thus, the windowing showed in Panel 6 will be applied.
Panel 6
Windowing of Weeks – Weekly eDiary Assessments
Days since IMP
First IMP
Second IMP
Third IMP
Fourth IMP
28 to 37
Week 5
Week 17
Week 29
Week 41
38 to 44
Week 6
Week 18
Week 30
Week 42
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Days since IMP
First IMP
Second IMP
Third IMP
Fourth IMP
45 to 51
Week 7
Week 19
Week 31
Week 43
52 to 58
Week 8
Week 20
Week 32
Week 44
59 to 65
Week 9
Week 21
Week 33
Week 45
66 to 72
Week 10
Week 22
Week 34
Week 46
73 to 79
Week 11
Week 23
Week 35 
Week 47
80 until the next IMP 
Week 12
Week 24
Week 36
Week 48
23.2.1.5
Calculation of Assessments for Intercurrent Events
Withdrawal from Treatment
When considering withdrawal from treatment data that are collected 3 months or more after 
the latest infusion will be excluded. Thus, for the daily entries, data occurring 84 days or more 
after the date for withdrawal from treatment will be removed. For the weekly entries, if at 
least one day of the 7-day period is covered by 84 days or more then data will be removed.
Use of Transitional Treatment
When considering the use of transitional treatment, data are excluded 7 days after the use of 
transitional treatment. Thus, for the daily entries, data that occur on 1 to 7 days after the date 
of use of transitional treatment will be removed. For the weekly entries, if the 7-day period is 
including at least 1 of the days in the 7-day period after use of transitional treatment data will 
be removed.
23.2.1.6
Calculation of Assessments for Sensitivity Analyses
When doing the sensitivity analyses of the use of transitional treatment and withdrawal from 
treatment data will contain all data when considering the prorating.
23.2.1.7
Response
For the periods of time a participant will be eligible to count as a responder if at least 50% of 
the weeks are observed and:

For 3-months intervals: at least 2 out of 3 months are observed

For 6-months intervals: at least 4 out of 6 months are observed

For 12-months intervals: at least 8 out of 12 months are observed
For participants fulfilling these criteria the average reduction of number of monthly attacks 
will be calculated and compared to the response threshold to evaluate if the participant is a 
responder. When finding the percentage of responders, the denominator will be the number of 
participants who fulfil these criteria.
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23.2.1.8
Conversion from cCH to eCH
Conversion is measured as ≥12 consecutive weeks with 0 attacks. For a participant to 
experience a conversion from cCH to eCH the following criteria must be fulfilled:

The series of weeks should start with a week with 0 attacks

The series of weeks should end with a week with 0 attacks

At least 50% of the of the weeks should be observed (corresponding to 7 weeks)

The series should consist of at least 13 consecutive weeks with 0 attacks or missing data 
fulfilling the above criteria.
23.2.1.9
Remission
For a participant to be in remission for the period listed in the endpoint the following should 
be fulfilled:

The series of weeks should start with a week with 0 attacks

The series of weeks should end with a week with 0 attacks

All observed weeks should have 0 attacks 

A maximum of 1 missing week

The series should consist of at least 4 consecutive weeks (which should all be in the period
listed in the endpoint)
23.2.2
1-year Exposure
For a participant to count as a having a 1-year exposure the following should be fulfilled:

A participant should have had 4 infusions with eptinezumab

A participant should have been followed for at least 365 days after their first infusion. 
Thus, there should be some data/contact/visit with a date that is 365 days or more after first 
infusion with eptinezumab
23.2.3
Country 
Countries with at least 20 participants will be kept individually, and countries with less than 
20 participants will be combined into one country called “other”.  
23.2.4
Use of Transitional Treatment
To address the endpoint Use of transitional treatment (Weeks 1-48), use of a transitional 
treatment will be collected from the “Transitional and Preventive Treatment for Cluster 
Headache Log” and in case of no findings, a participant will get a corresponding value of 0
for number of times a transitional therapy was used. 
If a participant withdraws, any transitional treatment that is collected from the form will be 
considered up until 48 weeks after the first IMP infusion.  
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23.2.5
Treatment Failure
A treatment failure is defined as stopping a preventive medication with the reason being lack 
of efficacy, safety/tolerability or contraindications.
23.2.6
Treatment Resistant
The definition of a participant being treatment resistant is inspired by a published guideline6
and the following criteria should be fulfilled for a participant to be treatment resistant:
1.
At least 12 severe CH attacks during the Screening Period
2.
At least three treatment failures with three different preventive medications prior to the 
Screening Visit
23.2.7
Sustained Response
A participant will be eligible to count as a sustained responder if:

The first month is a response

At least 50 % of the following months are observed

Month 12 should be observed

All observed months from the first month until Month 12 is a response
23.2.8
Maximum Score of Severity of Pain
The maximum score of severity of pain should be mild. In case of weeks with 0 attacks the 
severity will be considered to be mild or less. Furthermore, data need to have been observed 
for at least 4 days in a week to be able to assess if a participant fulfils the criterion about 
maximum score of severity being mild.
23.2.9
Patient Global Impression of Change (PGIC)
The PGIC is a single participant-reported item reflecting the participant’s impression of 
change in their disease status since the Baseline Visit (that is, in relation to activity 
limitations, symptoms, emotions, and overall quality of life). The item is rated on a 7-point 
scale, where a low score indicate improvement from 1 (very much improved) to 7 (very much 
worse).
23.2.10 Sleep Impact Scale (SIS)
The SIS7 is a participant-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”), 
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whereas satisfaction with sleep is rated on a 5-point scale ranging from 1 (very satisfied) to 5 
(very dissatisfied). Items within each domain were summed and transformed using the 
formula [(sum of the items – number of the items)/ range of the domain] * 100 yielding a 
score on a 0-100 scale.
A higher score indicated better quality of life (reverse scoring for the satisfaction with sleep 
domain).
Due to the technical build it will not be possible to have some missing values for a visit. 
Either all values will be there or none.
23.2.11 Euroqol 5 Dimension – 5 Levels (EQ-5D-5L)
The EQ-5D-5L8 is a participant-reported assessment designed to measure the participant’s 
well-being. It consists of 5 descriptive items (mobility, self-care, usual activities, 
pain/discomfort, and depression/anxiety) and a visual analogue scale (VAS) of the overall 
health state. Each descriptive item is rated on a 5-point index ranging from 1 (no problems) to 
5 (extreme problems) and a single summary index (from 0 to 1) can be calculated. The VAS 
ranges from 0 (worst imaginable health state) to 100 (best imaginable health state). The 
respondents rate their overall health on the day of the interview on a 0–100 hash-marked, 
vertical visual analogue scale.
Due to the technical build it will not be possible to have some missing values for a visit. 
Either all values will be there or none.
23.2.12 Health Care Resource Utilization (HCRU)
Cluster headache-specific healthcare resource utilization information will be collected in 
terms of outparticipant health care professional visits, emergency room visits, hospital 
admissions as well as number of overnight hospital stays during the past 4 weeks. Clinical site 
personnel and participants will be instructed to capture utilization that takes place outside of 
visits associated with their participation in the clinical trial.
23.2.13 Work Productivity and Activity Impairment: General Health version 2 
(WPAI:GH2.0)
The WPAI:GH2.09 is a participant 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 participant’s condition, or due to other reasons; and 2 visual numerical scales to 
assess how much the participant’s condition affects their productivity at work and their ability 
to complete normal daily activities.
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The derivation of the WPAI:GH2.0 sub-scores10 is given in Panel 7, where Q1-Q6 refers to 
question 1-6 in the questionnaire.
Panel 7
Derivation of WPAI:GH2.0 sub-scores
Sub-score
Description
Derivation
Absenteeism
Percent work time missed due to 
health problems
100*Q2/(Q2 + Q4)
Presenteeism
Percent impairment while 
working due to health problems
100*Q5/10
Work productivity loss
Percent overall work impairment 
due to health problems
100 ∗
	
	 
 + 1 −
	
	 
  ∗


Activity impairment
Percent activity impairment due 
to health problems
100*Q6/10
If the answer to Q1 (Are you currently employed (working for pay)?) is ‘Yes’ but Q2 (During 
the past seven days, how many hours did you miss from work because of your health 
problems?) and Q4 (During the past seven days, how many hours did you actually work?) are 
both 0, then the derived scores for Absenteeism and Work productivity loss score will be set 
to missing.
23.2.14 Withdrawal from Treatment
When a participant withdraws from study it is not necessary to also fill out a “withdrawal 
from treatment” form. Thus, some participants will only have entered information about 
withdrawal from study. However, when a participant withdraws from study prior to receiving 
the fourth infusion with eptinezumab, a withdrawal from study is also relevant to be regarded 
as a withdrawal from treatment. Therefore, when a participant withdraws from study prior to 
receiving the fourth infusion and if there is no withdrawal from treatment for that participant
the withdrawal from study will be used to define withdrawal from treatment. The time of 
withdrawal from treatment will be the same as the time of withdrawal from study. If the
primary reason for withdrawal from study is either “lack of efficacy” or “adverse events” then 
the primary reason for withdrawal from treatment will be the same as the primary reason for 
withdrawal from study. All other primary reasons for withdrawal from study will be defined 
as “other” for the primary reason for withdrawal from treatment. All other reasons for 
withdrawal will not be inherited from withdrawal from study to withdrawal from treatment.
When the “Withdrawal from treatment” form was filled out all reasons for withdrawal from 
treatment will be used.
23.3
Assigning Data to Visits
See section 3.1 for definition of baseline values.
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23.3.1
Clinical Outcome Assessments (COAs) - Scales
For a participant withdrawing prior to the Completion Visit, the Withdrawal Visit will also 
include efficacy evaluations (PGIC, SIS, EQ-5D-5L, HCRU, and WPAI:GH2.0).
Assessments from PGIC will be assigned to a Visit based on the windowing in Panel 8. 
Assessments from SIS will be assigned to a Visit based on the windowing in Panel 9.
Assessments from EQ-5D-5L, HCRU, and WPAI:GH2.0 will be assigned to a Visit based on 
the windowing in Panel 10. In case of duplicate scale assessments in relation to a nominal 
visit the assessments from the Withdrawal Visit will be used. 
Panel 8
Visit Windows – PGIC
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
Visit 3
4
28
1-42
Visit 4
8
56
43-70
Visit 5
12
84
71-98
Visit 6
16
112
99-126
Visit 7
20
140
127-154
Visit 8
24
168
155-182
Visit 9
28
196
183-210
Visit 10
32
224
211-238
Visit 11
36
252
239-266
Visit 12
40
280
267-294
Visit 13
44
308
295-322
Visit 14
48
336
> 322 
Panel 9
Visit Windows – SIS
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
Visit 3 
4
28
1-56
Visit 5
12
84
57-98
Visit 6
16
112
99-140
Visit 8
24
168
141-182
Visit 9
28
196
183-224
Visit 11
36
252
225-266
Visit 12
40
280
267-308
Visit 14
48
336
>308
Panel 10
Visit Windows – EQ-5D-5L, HCRU, and WPAI:GH2.0
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
Visit 3 
4
28
<84
Visit 6
16
112
84 <= and <168
Visit 9
28
196
168 <= and < 252
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Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
Visit 12
40
280
252 <= and < 308 
Visit 14
48
336
308 <=   
Unscheduled visits will not contain assessments of the COAs mentioned above. In relation to 
the nominal visits post-baseline, a participant can complete their COAs 3 days before the 
visit. In case of duplicate scale assessments in relation to a nominal visit, i.e. if a participant
fills out the scales 3 days before the visit and the visit is postponed afterwards implying that 
the participant has to complete the COA again, the latest assessment will be used.
Assessments done at Visit 2 for EQ-5D-5L, SIS, HCRU, and WPAI:GH2.0 will be assigned 
as the baseline value regardless of timing in relation to the IMP infusion. 
23.3.2
Safety Variables
If there is more than one assessment at a visit (either due to multiple assessments or because 
an unscheduled or withdrawal visit assessment is mapped to a nominal visit with an already 
existing value) the value that will be used in summary tables by visit will be the one closest to 
the nominal day for the visit but prioritizing values from scheduled visits above values from 
withdrawal or unscheduled visits. In the ordering of multiple values, assessments without 
recorded time will come after assessments with recorded time and the first in the ordering will 
be picked. 
Laboratory Tests and ECG
Assessments of laboratory tests and ECGs at unscheduled visits and withdrawal visits will be 
assigned to a nominal visit according to the visit windowing specified in Panel 11 for
participants in the APTS. Assessments for participants not receiving any infusions of IMP 
will be assigned to the Baseline Visit. 
Panel 11
Visit Windows – Laboratory tests, ECG
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
Visit 1 (Screening Visit)
-4
-28
Before day 0 and before 
first IMP infusion
Visit 2 (Baseline Visit)
0
0
Same day as first IMP 
infusion (Day 0) and prior 
to IMP infusion on that 
date
Visit 5
12
84
After start of first IMP 
infusion to start of Visit 5 
IMP infusion
Visit 8
24
168
After start of Visit 5 IMP 
infusion to start of Visit 8 
IMP infusion
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Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
Visit 11
36
252
After start of Visit 8 IMP 
infusion to start of Visit 
11 IMP infusion
Visit 14
48
336
After start of Visit 11 IMP 
infusion 
Vital Signs
Vital signs will be assessed before and after infusion at nominal visits. For unscheduled or 
withdrawal visit assessments of vital signs, the values will be assigned a nominal visit 
according to Panel 12, and for scheduled visits where no IMP was given the assessment will 
be windowed to the pre-dose assessment at the nominal visit.
Panel 12
Visit Windows – Vital Signs (Pulse rate, Blood Pressure, Temperature)
Nominal Visit Number
Nominal Visit Week
Nominal Visit Day
Time Window
Visit 1 (Screening Visit)
-4
-28
Before day 0 and before 
first IMP infusion
Visit 2 (Baseline Visit) pre-dose
0
0
Same day as first IMP 
infusion (Day 0) and prior 
to IMP infusion on that 
date
Visit 2 (Baseline Visit) post-dose
0
0
After start of first IMP 
infusion to day 42
Visit 5 pre-dose
12
84
Day 43 to start of Visit 5 
IMP infusion
Visit 5 post-dose
12
84
After start of Visit 5 IMP 
infusion to day 126 
Visit 8 pre-dose
24
168
Day 127 to start of Visit 8 
IMP infusion
Visit 8 post-dose
24
168
After start of Visit 8 IMP 
infusion to day 210
Visit 11 pre-dose
36
252
Day 211 to start of Visit 
11 IMP infusion
Visit 11 post-dose
36
252
After start of Visit 11 IMP 
infusion to day 294
Visit 14
48
336
> 294
Height and Weight
Height is only assessed at the screening visit and weight is assessed once at each nominal
visit. Windowing of these parameters will follow the windowing used for Laboratory tests and 
ECG.
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23.4
Handling Missing or Incomplete Dates/Times
23.4.1
Withdrawal Date
Missing withdrawal dates will not be imputed and time to withdrawal from study or treatment 
will not be calculated for missing withdrawal dates.
23.4.2
Medical Disorder Start and Stop Dates
Incomplete dates will not be imputed. Classification of events into concurrent medical 
disorders or past disorders will be based on the reported ongoing status.
23.4.3
Medication Start and Stop Dates
Imputation of incomplete or partially missing dates will be performed in order to document 
the assigned categories specified in chapter 10.
The algorithm for imputing the start dates will follow the one used for imputing adverse event
start dates, see section 23.4.4. Furthermore when the start date is completely missing for 
medications collected at the Screening Visit, the medication start date is imputed with the date 
of the Screening Visit.
For imputing stop dates, the following will apply, where UK and UKN indicate unknown or 
missing day and month, respectively:

UK-MMM-YYYY: Medication end date is imputed with the last day of the month

UK-UKN-YYYY: Medication end date is imputed with 31-DEC-YYYY

If the stop date collected at the Screening Visit is completely missing and the medication is 
not being recorded as an ongoing medication, then the medication stop date is imputed 
with the date of the Screening Visit.
23.4.4
Adverse Event Start and Stop Dates
Imputation of partially or completely missing dates will be included in data in order to 
document the classification of the treatment emergent status and assignment of the adverse 
event to a period. For an adverse event with an imputed start date, the classification of 
treatment emergent will depend only on whether the imputed date is the same as the date(s) of 
infusion and not the timepoint of the infusion, since start times for adverse events will not be 
imputed. No duration will be calculated for adverse events with incomplete start-or-stop dates 
or for ongoing adverse events.
Imputation will follow the algorithm below. If an imputed start date after this procedure is 
after the end date, the start date will be set to the end date. 
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Start Dates
Participants with no IMP infusion
For participants who have not been treated, the imputation of AE start date will be performed 
as follows, where UK and UKN indicate unknown or missing day and month, respectively:

UK-MMM-YYYY: The start date will be imputed with either the 1st of the month, or date 
of the Baseline Visit. Date of the Baseline Visit will be used if that is the later of the two 
and if it is within the specified month and year

UK-UKN-YYYY: The start date will be imputed with either JAN 1, or date of the Baseline 
Visit. Date of the Baseline Visit will be used if it is within the specified year
If the AE start date is completely missing, it will be set equal to the date of the Baseline Visit.
Participants who received at least one IMP infusion
For participants, who have been treated, the imputation of AE start dates will be performed as 
follows:

UK-MMM-YYYY:
o If the year and month are equal to the year and month of treatment start date, the 
adverse event start date is imputed with the date of first dose of IMP
o If the year is equal to the year of treatment start date: If the month is prior to the 
treatment start date, the adverse event start date is imputed with the last day of the 
month. If the month is equal to the month of the treatment start date, see above. If the 
month is after the month of the treatment start date, the adverse event start date is 
imputed with the first day of the month
o If the year is prior to treatment start date, the adverse event start date is imputed with the 
last day of the month
o If the year is after the year of treatment start date, the adverse event start date is imputed 
with the first day of the month

UK-UKN-YYYY:
o If the year is equal to the year of treatment start date, the adverse event start date is 
imputed with treatment start date
o If the year is prior to the year of treatment start date, the adverse event start date is 
imputed with 31-DEC-YYYY
o If the year is after the year of treatment start date, the adverse event start date is imputed 
with 01-JAN-YYYY

DD-UKN-YYYY:
o If the year is equal to the year of treatment start date, the adverse event start date is 
imputed with treatment start date
o If the year is prior to the year of treatment start date, the adverse event start date is 
imputed with DD-DEC-YYYY
o If the year is after the year of treatment start date, the adverse event start date is imputed 
with DD-JAN-YYYY
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
If the AE start date is completely missing:
o If the AE stop date is not missing and is before the treatment start date, the adverse 
event start date is imputed with the AE stop date
o If the AE stop date is not missing and is after the treatment start date, the adverse event 
start date is imputed with the treatment start date
o If the AE stop date is missing (either completely or partially), the adverse event start 
date is imputed with the treatment start date
End Dates
Missing AE end dates will not be imputed. 
Incomplete Intensity Change Dates
If the day is missing in a date of intensity change for an adverse event, the date will be 
imputed using the same algorithm as described above for incomplete adverse event start dates.
If this results in an imputed start date that is after the end date of the original event or after an 
intensity change that comes after the intensity change in question, the start date will be 
imputed with the end date of the original event or the date of the later intensity or change.
23.5
Data with Multiple Records
23.5.1
Dose Changes in Medication
Dose changes in medications are recorded on multiple rows in the dataset, with different start 
and stop dates. When classifying medications into categories (see chapter 10), each dose is 
considered a separate medication, and the same medication can be assigned to several 
categories for the same participant. Within a category, multiple entries contribute as a single 
count.
23.5.2
Treatment-emergent AEs and Changes in Intensity or Seriousness of Adverse 
Events
An AE spans an interval in time, and in data it is potentially divided into several sub-intervals 
to ensure that within each sub-interval the status is the same for the whole interval. This could 
lead to multiple records for an AE as described in Panel 13.
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Panel 13
Definition of Multiple Records
Event
Details
TEAE flag
AE starts at or after first 
dose of IMP
AE event created (start and possibly stop 
dates and AE characteristics are described) 
TRTEMFL=”Y”
Change in intensity
AE is split in 2 rows: Before and after 
change, so each part has the correct 
intensity
If prior to first IMP => TRTEMFL 
= “ ”
If at or after first IMP AND
intensity increase => 
TRTEMFL=”Y”
If at or after first IMP AND
intensity decrease => TRTEMFL =” 
“
AE becomes SAE
If an existing AE becomes an SAE the AE 
is split in 2 rows: Before and after the 
datetime of the SAE occurrence. The AE is 
marked as SAE from this point and 
onwards.
If prior to first IMP => TRTEMFL 
= “ “
If at or after first IMP => 
TRTEMFL=”Y”
Events that do not happen simultaneously and with same precision on datetime, handle individually as above. 
Unknown time will be considered later than known time points.
For events where multiple changes occur that do not happen simultaneously, extra rows are added for each 
change; for instance, will an AE with an intensity change and a change in seriousness be split into 3 rows: 1 for 
the original AE when it starts, 1 for the intensity change and 1 for the serious change.
Events that happen 
simultaneously:
SAE and change in 
intensity
An existing AE will be split in 2 rows: 
Before and after the event
If prior to first IMP => TRTEMFL 
= “ ”
If at or after first IMP => 
TRTEMFL=”Y” (due to SAE, 
regardless of the direction of the 
intensity change)
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References
1. 
Mark Oberman, Steffen Nägel, Claudia Ose, Nilüfer Sonuc, André Scherag, Peter Storch, Charly 
Gaul, Andreas Böger, Torsten Kranya, Jan-Peter Jansen, Andreas Straube, Tobias Freilinger, 
Holger Kaube, Tim P Jürgens, Hans-Christoph Diener, Zaza Katsarava, Christoph Kleinschnitz, 
Dagny Holle. Safety and efficacy of prednisone versus placebo in short-term prevention of 
episodic cluster headache: a multicenter, double-blind, randomized controlled trial. The Lancet 
Neurology 2021;20:29-37
2.
United States Food and Drug Administration (US FDA). Guidance for Industry: Drug-induced 
liver injury: premarketing clinical evaluation. July 2009.
3. 
ICH. ICH Harmonised Tripartite Guideline E1: The extent of population exposure to assess 
clinical safety for drugs intended for long-term treatment of non-life-threatening conditions. 27 
October 1994
4. 
Dodick DW, Goadsby PJ, Lucas C, Jensen R, Bardos JN, Martinez JM, et al. Phase 3 
randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: 
Results from 3-month double-blind treatment. Cephalalgia. 2020 Aug;40(9):935-948.
5. 
Clinical trial results: A multicenter, randomized, double-blind, double-dummy, placebo-
controlled, parallel-group study comparing the efficacy and safety of 2 dose regimens 
(intravenous/subcutaneous and subcutaneous) of TEV-48125 versus placebo for the prevention of 
chronic Cluster Headache. Version 1. 3 August 2019.
6. 
Dimos D Mitsikostas, Lars Edvinsson, Rigmor H Jensen et al. Refractory chronic cluster 
headache: a consensus statement on clinical definition from the European Headache Federation. 
The Journal of Headache and Pain 2014;15:79-82
7.
Crawford B, Burgess S, Burell A, Tellefsen C. Development and validation of the sleep impact 
scale for insomnia. Value in Health, 2007;10:A304. 
8.
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of Life 
Research. 2011;20:1727–1736.
9.
Reilly MC, Zbrozek AS, Dukes, EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics. 1993;4(5):353–365.
10. Reilly Associates. WPAI Scoring.[Internet] reillyassociates.net/WPAI_Scoring.html
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Appendix I
Statistical Analysis Plan
Authentication and Authorization
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Statistical Analysis Plan
Authentication and Authorization
Trial title:
Interventional, open-label, fixed-dose multiple administration study to evaluate 
long-term treatment with eptinezumab in participants with chronic cluster headache
Trial No.:
19385A
SAP date:
29 June 2023
This document has been signed electronically. The signatories are listed below.
Authentication
Authorization
PPD
PPD
PPD
PPD
PPD
PPD
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Appendix II
SAS® Code
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SAS® Code
Short-term Efficacy Estimand
The SAS® code for the analysis of the short-term efficacy estimand described in Section 
13.5.1 is given below. Here it is assumed that the ordering of the week factor is week 1, week 
2, week 3, week 4, …
proc mixed data=DPS2 method = REML noclprint;
class COUNTRG1(ref = "OTHER") AVISITN USUBJID;
model CHG = COUNTRG1 AVISITN LOGBASE LOGBASE*AVISITN / DDFM = KR;
repeated AVISITN / type=UN subject=USUBJID;
lsmestimate AVISITN 'Change from Baseline in Weekly Attacks: Weeks 1-4'
           [1, 1] [1, 2] [1, 3] [1, 4]/ divisor = 4; 
run;
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Appendix III
PCS Criteria
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PCS Criteria
Table 1
PCS Criteria for Clinical Safety Laboratory Tests
Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
Haematology / Coagulation
B-haemoglobin
HGB
g/L
≤ 95 (women)
≥ 165 (women)
≤ 115 (men)
≥ 185 (men)
B-erythrocytes (red cell count)
RBC
x 10E12/L
≤ 3.5 (women)
≥ 6.0 (women)
≤ 3.8 (men)
≥ 7.0 (men)
B-haematocrit (packed cell 
volume)
HCT
V/V
≤ 0.32 (women)
≥ 0.50 (women)
≤ 0.37 (men)
≥ 0.55 (men)
B-MCV (mean cell volume)
MCV
fL
≤ 0.8 x LLN
≥ 1.2 x ULN
B-total leucocyte (white cell 
count)
WBC
x 10E9/L
≤ 2.8
≥ 16
B-neutrophils/leucocytes
NEUTLE
%
≤ 20
≥ 85
B-eosinophils/leucocytes
EOSLE
%
≥ 10
B-basophils/leucocytes
BASOLE
%
≥ 10
B-lymphocytes/leucocytes
LYMLE
%
≤ 10
≥ 75
B-monocytes/leucocytes
MONOLE
%
≥ 15
B-thrombocytes (platelet count)
PLAT
x 10E9/L
≤ 75
≥ 600
P-INR (prothrombin ratio)
INR
Ratio
≥ 2.0
B-prothrombin time
PT
Sec
≥ 18
Liver
S-aspartate aminotransferase
AST
I/L
≥ 3 × ULN
S-alanine aminotransferase
ALT
I/L
≥ 3 × ULN
S-bilirubin
BILI
μmol/L
≥ 34
S-bilirubin, direct
BILDIR
μmol/L
≥ 12
S-bilirubin, indirect
BILIND
μmol/L
≥ 22
S-alkaline phosphatase
ALP
I/L
≥ 3 × ULN
S-gamma glutamyl transferase
GGT
I/L
≥ 200
S-alpha-glutathione S-transferase 
(alpha-GST)
GSTAL
μg/L
≥ 20
Kidney
S-creatinine
CREAT
μmol/L
≥ 1.5 x ULN
B-urea nitrogen (BUN)
BUN
mmol/L
≥ 11
S-uric acid (urate)
URATE
μmol/L
≥ 510 (women)
≥ 630 (men)
Electrolytes
S-sodium (natrium)
SODIUM
mmol/L
≤ 125
≥ 155
S-potassium (kalium)
K
mmol/L
≤ 3.0
≥ 6.0
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Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
S-calcium
CA
mmol/L
≤ 1.8
≥ 3.0
S-chloride
CL
mmol/L
≤ 90
≥ 117
S-magnesium
MG
mmol/L
≤ 0.6
≥ 1.3
S-phosphate (phosphorus, 
(inorganic)
PHOS
mmol/L
≤ 0.65
≥ 1.95
S-bicarbonate
BICARB
mmol/L
≤ 12
≥ 38
Endocrine / Metabolic
B-glucose, non-fasting/unknown
GLUC
mmol/L
≤ 3.4
≥ 9.4
B-glucose, fasting
GLUC
mmol/L
≤ 3.0
≥ 6.0
S-glucose, non-fasting/unknown
GLUC
mmol/L
≤ 3.9
≥11.1
S-glucose, fasting
GLUC
mmol/L
≤ 3.5
≥ 7.0
B-glycosylated haemoglobin, 
fasting
HBA1C
Hb fract.
≥ 6.5
S-prolactin
PROLCTN
mIU/L
≥ 1350
S-thyrotropin/TSH
TSH
mIU/L
≤ 0.3
≥ 5.5
S-protein (total)
PROT
g/L
≤ 45
≥ 95
S-albumin
ALB
g/L
≤ 27
Lipids
S-cholesterol total, non-
fasting/unknown
CHOL
mmol/L
≥ 7.8
S-cholesterol total, fasting
CHOL
mmol/L
≥ 6.2
S-triglycerides, non-
fasting/unknown
TRIG
mmol/L
≥ 5.65
S-triglycerides, fasting
TRIG
mmol/L
≥ 4.2
S-LDL cholesterol, non-
fasting/unknown
LDL
mmol/L
≥ 5.3
S-LDL cholesterol, fasting
LDL
mmol/L
≥ 4.9
S-HDL cholesterol, non-
fasting/unknown
HDL
mmol/L
≤ 0.8
S-HDL cholesterol, fasting
HDL
mmol/L
≤ 0.9
Cardiac/Skeletal/Muscle
S-creatine kinase (total)
CK
I/L
≥ 400 (women)
≥ 750 (men)
S-creatine kinase MB isoenzyme
CKMB
μg/L
≥ 8.5 or
CKMBCK
%
≥ 3.5% of total 
CK
S-lactate dehydrogenase (total)
LDH
IU/L
≥ 750
S-troponin I
TROPONI
μg/L
≥ 1.5
S-troponin T
TROPONT
μg/L
≥ 0.4
Infection
S-C-reactive protein
CRP
mg/L
≥ 25
S-globulin (total)
GLOBUL
g/L
≤ 15
≥ 55
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Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
Urine
Urinary pH
PH
≤ 4
≥ 9
S=serum; B=whole blood; U=urine
Table 2
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference
Variable
CDISC Term
Unit
PCS Low
PCS High
Waist circumference
WSTCIR
Cm
decrease ≥ 7%
increase ≥ 7%
Weight
WEIGHT
Kg
decrease ≥ 7%
increase ≥ 7%
Body Mass Index
BMI
kg/m2
decrease ≥ 7%
increase ≥ 7%
Pulse rate, 
supine/sitting/unknown
PULSE
beats/min
< 50 and
decrease ≥ 15
≥ 120 and
increase ≥ 15
Diastolic blood pressure,
supine/sitting/unknown
DIABP
mmHg
≤ 50 and
decrease ≥ 15
≥ 105 and
increase ≥ 15
Systolic blood pressure,
supine/sitting/unknown
SYSBP
mmHg
≤ 90 and
decrease ≥ 20
≥ 180 and
increase ≥ 20
Orthostatic systolic blood 
pressure
OBP
mmHg
≤ -30
Orthostatic pulse rate
OPR
beats/min
≥ 20
Temperature
TEMP
ºC
decrease ≥ 2
≥ 38.3 and
increase ≥ 2
Increase/decrease is relative to the baseline value.
Table 3
PCS Criteria for ECG Parameters
ECG Parameter
CDISC Term
Unit
PCS Low
PCS High
Absolute Time Interval
PR interval
PRMEAN
Msec
≥ 260
QRS interval
QRSDUR
Msec
≥ 150
QT interval
QTMEAN
Msec
≥ 500
Derived Time Interval
Heart rate
HRMEAN
beats/min
< 50 and
decrease ≥ 15
≥ 120 and
increase ≥ 15
QTcB interval
QTCB
Msec
< 300
> 500 or
increase > 60
QTcF interval
QTCF
Msec
< 300
> 500 or
increase > 60
Increase/decrease is relative to the baseline value.
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Appendix IV
Trial flow chart
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Trial flow chart
Table 4
Trial 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













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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
SIS k










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



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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 
metabolomics/proteomics
(plasma) s



Blood sampling for phar-
macogenetics (DNA) 
(optional) t

Blood sampling for pos-
sible future ADA assess-
ment u






Other Trial 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 
Utilization; IMP = investigational medicinal product; IV = intravenous; NAbs = neutralizing antibodies; 
PGIC = Patient Global Impression of Change; ePRO = electronic participant-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 participant will be contacted for eDiary compliance check, to ensure that the selected 
assessments have been completed and for collection of relevant information such as adverse events and con-
comitant medications.
c
The SFU Visit should be scheduled 20 weeks (5 half-lives) after the last eptinezumab administration.
d
Participants who withdraw from 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 
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planned to maintain the visit schedule relative to the Baseline Visit (Day 0/Visit 2).
f
At the Screening Visit, the participant 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 ICFs may be different. Under exceptional circumstances, the discussion with the participants about the In-
formed Consent Form(s) can be done as a virtual clinic visit and the Informed Consent Form(s) can be pro-
vided remotely in line with the US FDA and EMA guidances. According to the EMA guidance, this could 
comprise contacting the participants via phone or video-calls and obtaining oral consents, to be documented 
in the participants' 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 participants are back at the clinical sites.
g
Participants 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 
documented 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 participant must be assisted with the provisioning and training of the eDiary and 
ePROs. Details will be provided in a separate training module.
j
Participants 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
Participants 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 trial visits, ongoing evaluation of eDi-
ary compliance will be performed by the clinical site (based on eDiary reporting) and more frequent contact 
with participants 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 participant with-
draws) sample will only be drawn for the safety ADA/NAb assessments when applicable.
v
Participants must be monitored during the infusion and for a period of 1 hour from the end of infusion. Par-
ticipants will be requested to stay longer should the investigator or designee determine this is clinically 
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warranted.
w The eDiary closeout will take place at Completion Visit (Week 48/Visit 14) / Withdrawal Visit (for partici-
pants 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 con-
ducted using serum beta-human chorionic gonadotropin (β-hCG). At all other visits, urine pregnancy testing 
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 participant 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 participant on the date of that first assessment, which is considered 
as the first day of the 28-day Screening Period.
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Appendix V
Adverse Events of Special Interest
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Adverse Events of Special Interest
Table 5
Adverse Events of Special Interest
Event types
SMQ/HLT/HLGT
Additional criteria
Cardio/cerebrovascular events
Cardiac arrhythmias (SMQ) 
(Narrow)
Cardiac failure (SMQ) (Narrow)
Cardiomyopathy (SMQ) (Narrow)
Central nervous system vascular 
disorders (SMQ) (Narrow)
Embolic and thrombotic events 
(SMQ) (Narrow)
Hypertension (SMQ) (Narrow)
Ischaemic heart disease (SMQ) 
(Narrow)
Pulmonary hypertension (SMQ) 
(Narrow)
Torsade de pointes/QT prolongation 
(SMQ) (Narrow)
Events associated with Suicide
Suicide/self-injury (SMQ) (Narrow)
Events potentially associated with 
Trial Drug Infusion
Angioedema and urticaria (HLGT)
(primary PTs only)
TEAE on the day of dosing after the 
infusion was started or during the 7 
days after dosing
Bronchial disorders (excl 
neoplasms) (HLGT) (primary PTs 
only)
TEAE on the day of dosing after the 
infusion was started
Infusion site reactions (HLT) 
(primary PTs only)
TEAE on the day of dosing after the 
infusion was started or during the 7 
days after dosing
Oral soft tissue signs and symptoms 
(HLT) (primary PTs only)
TEAE on the day of dosing after the 
infusion was started
Oral soft tissue swelling and 
oedema (HLT) (primary PTs only)
TEAE on the day of dosing after the 
infusion was started
Pruritus NEC (HLT) (primary PTs 
only)
TEAE on the day of dosing after the 
infusion was started or during the 7 
days after dosing
Rashes, eruptions and exanthems 
NEC (HLT) (primary PTs only)
TEAE on the day of dosing after the 
infusion was started or during the 7 
days after dosing
Respiratory disorders NEC (HLGT) 
(primary PTs only)
TEAE on the day of dosing after the 
infusion was started
Respiratory tract signs and 
symptoms (HLGT) (primary PTs 
only)
TEAE on the day of dosing after the 
infusion was started
Upper respiratory tract disorders 
(excl infections) (HLGT) (primary 
PTs only)
TEAE on the day of dosing after the 
infusion was started
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Event types
SMQ/HLT/HLGT
Additional criteria
Hepatic events
Drug related hepatic disorders -
comprehensive search (SMQ) 
(Narrow)
Hypersensitivity and Anaphylactic 
Reactions
Anaphylactic reaction (SMQ) 
(Narrow)
Angioedema (SMQ) (Narrow)
Hypersensitivity (SMQ) (Narrow)
Seizures
Convulsions (SMQ) (Narrow)
v. 2.0
CLI_02072524

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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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Version: 
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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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References
1. 
ICH. ICH Harmonised Tripartite Guideline E1: The extent of population exposure to assess 
clinical safety for drugs intended for long-term treatment of non-life-threatening conditions. 27 
October 1994
2. 
Dodick DW, Goadsby PJ, Lucas C, Jensen R, Bardos JN, Martinez JM, et al. Phase 3 
randomized, placebo-controlled study of galcanezumab in patients with chronic cluster headache: 
Results from 3-month double-blind treatment. Cephalalgia. 2020 Aug;40(9):935-948.
3. 
Clinical trial results: A multicenter, randomized, double-blind, double-dummy, placebo-
controlled, parallel-group study comparing the efficacy and safety of 2 dose regimens 
(intravenous/subcutaneous and subcutaneous) of TEV-48125 versus placebo for the prevention of 
chronic Cluster Headache. Version 1. 3 August 2019.
4. 
International Headache Society (IHS), Headache Classification Committee. The International 
Classification of Headache Disorders, 3rd edition 2018 (ICHD-3 2018).
5.
Jensen RM, Lyngberg A, Jensen RH. Burden of Custer headache. Cephalalgia. 2007 
Jun;27(6):535-541.
6.
Ford JH, Nero D, Kim G, Chu BC, Fowler R, Ahl J, et al. Societal burden of cluster headache in 
the United States: a descriptive economic analysis. J Med Econ. 2018 Jan;21(1):107-111.
7.
Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: a 
meta-analysis of population-based studies. Cephalalgia. 2008 Jun;28(6):614-618.
8.
Lund N, Barloese M, Petersen A, Haddock B, Jensen R. Chronobiology differs between men and 
women with cluster headache, clinical phenotype does not. Neurology. 2017 Mar;88(11):1069-
1076.
9.
Torelli P, Manzoni GC. Pain and behaviour in cluster headache. A prospective study and review 
of the literature. Funct Neurol. 2003 Oct-Dec;18(4):205-210.
10. Ekbom K, Monstad I, Prusinski A, Cole JA, Pilgrim AJ, Noronha D. Subcutaneous sumatriptan in
the acute treatment of cluster headache: a dose comparison study. The Sumatriptan Cluster
Headache Study Group. Acta Neurol Scand. 1993 Jul;88(1):63-69.
11. Law S, Derry S, Moore RA. Triptans for acute cluster headache. Cochrane Database Syst Rev.
2013 Jul;(7):CD008042.
12. Treatment of acute cluster headache with sumatriptan. The Sumatriptan Cluster Headache Study
Group. N Engl J Med. 1991 Aug;325(5):322-326.
13. Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a
randomized trial. JAMA. 2009 Dec;302(22):2451-2457.
14. Fogan L. Treatment of cluster headache. A double-blind comparison of oxygen v air inhalation.
Arch Neurol. 1985 Apr;42(4):362-363.
15. Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache. 1981
Jan;21(1):1-4.
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16. Petersen AS, Barloese MC, Lund NL, Jensen RH. Oxygen therapy for cluster headache. A mask
comparison trial. A single-blinded, placebo-controlled, crossover study. Cephalalgia. 2017
Mar;37(3):214-224.
17. Afridi SK, Shields KG, Bhola R, Goadsby PJ. Greater occipital nerve injection in primary
headache syndromes--prolonged effects from a single injection. Pain. 2006 May;122(1-2):126-
129.
18. Leroux E, Valade D, Taifas I, Vicaut E, Chagnon M, Roos C, et al. Suboccipital steroid injections 
for transitional treatment of patients with more than two cluster headache attacks per day: a 
randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2011 Oct;10(10):891-897.
19. Petersen AS, Barloese MCJ, Snoer A, Soerensen AMS, Jensen RH. Verapamil and cluster
headache: still a mystery. A narrative review of efficacy, mechanisms and perspectives.
Headache. 2019 Sep;59(8):1198-1211.
20. Tfelt-Hansen PC, Jensen RH. Management of cluster headache. CNS Drugs. 2012 Jul;26(7):571-
580.
21. Huang WY, Lo MC, Wang SJ, Tsai JJ, Wu HM. Topiramate in prevention of cluster headache in
the Taiwanese. Neurol India. 2010 Mar-Apr;58(2):284-287.
22. May A, Schwedt TJ, Magis D, Pozo-Rosich P, Evers S, Wang SJ. Cluster headache. Nat Rev Dis
Primers. 2018 Mar;4:18006.
23. Edvinsson L, Goadsby PJ. Neuropeptides in migraine and cluster headache. Cephalalgia. 1994
Oct;14(5):320-327.
24. Snoer A, Vollesen ALH, Beske RP, Guo S, Hoffmann J, Fahrenkrug J, et al. Calcitonin-gene
related peptide and disease activity in cluster headache. Cephalalgia. 2019 Apr;39(5):575-584.
25. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of
humans during migraine headache. Ann Neurol. 1990 Aug;28(2):183-187.
26. Vollesen ALH, Snoer A, Beske RP, Guo S, Hoffmann J, Jensen RH, et al. Effect of infusion of 
calcitonin gene-related peptide on cluster headache attacks: A randomized clinical trial. JAMA 
Neurol. 2018 Oct;75(10):1187-1197.
27. Ashina, M, Saper J, Cady R, Schaeffler BA, Biondi DM, Hirman J, et al. Eptinezumab in episodic 
migraine: A randomized, double-blind, placebo-controlled study (PROMISE-1). Cephalalgia. 
2020 Mar;40(3):251-254.
28. Lipton RB, Goadsby PJ, Smith J, Schaeffler BA, Biondi DM, Hirman J, et al. Efficacy and safety 
of eptinezumab in patients with chronic migraine: PROMISE-2. Neurology. 2020 Mar 
31;94(13):e1365-e1377. 
29. H. Lundbeck A/S. Investigator’s Brochure: eptinezumab. current version.
30. Gupta R, Levin E, Wu JJ, Koo J, Liao W. An update on drug-drug interactions with biologics for 
the treatment of moderate-to-severe psoriasis. J Dermatolog Treat. 2014;25(1):87-89.
31. ClinicalTrials.gov Identifier: NCT04152083.
32. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and 
pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548-558. 
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33. Rozen TD, Fishman RS. Cluster headache in the United States of America: Demographics, 
clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012 Jan;52(1):99-
113.
34. World Medical Association (WMA). Declaration of Helsinki: Ethical principles for medical 
research involving human subjects. [Internet] wma.net/policies-post/wma-declaration-of-helsinki-
ethical-principles-for-medical-research-involving-human-subjects/
35. ICH. ICH Harmonised Guideline E6(R2): Integrated addendum to ICH E6(R1): Guideline for 
Good Clinical Practice. November 2016.
36. United States Food and Drug Administration (US FDA). Guidance for Industry, Investigators, 
and Institutional Review Boards: Conduct of clinical trials of medical products during the 
COVID-19 public health emergency. March 2020 (updated on December 4, 2020).
37. European Medicines Agency (EMA). Guidance on the management of clinical trials during the 
COVID-19 (coronavirus) pandemic. Version 4. 04 February 2021.
38. Mitsikostas DD, Edvinsson L, Jensen RH, Katsarava Z, Lampl C, Negro A, et al. Refractory 
chronic cluster headache: a consensus statement on clinical definition from the European 
Headache Federation. J Headache Pain. 2014 Nov 27;15(1):79.
39. Dodick DW, Rozen TD, Goadsby PJ, Silberstein SD. Cluster headache. Cephalalgia. 2000
Nov;20(9):787-803.
40. Lund N, Petersen A, Snoer A, Jensen RH, Barloese M. Cluster headache is associated with
unhealthy lifestyle and lifestyle-related comorbid diseases: Results from the Danish Cluster
Headache Survey. Cephalalgia. 2019 Feb;39(2):254-263.
41. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of
galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3
randomized controlled clinical trial. Cephalalgia. 2018 Jul;38(8):1442-1454.
42. Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic
migraine: The randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018
Dec;91(24):e2211-e2221.
43. Goadsby PJ, Dodick DW, Leone M, Bardos JN, Oakes TM, Millen BA, et al. Trial of 
galcanezumab in prevention of episodic cluster headache. N Engl J Med. 2019 Jul 11;381(2):132-
141.
44. Caceres MC, Guerrero-Matin J, Pérez-Civantos D, Palomo-Lopez P, Delgado-Mingorance JI, 
Duran-Gomez N. The importance of early identification of infusion-related reactions to 
monoclonal antibodies. Ther Clin Risk Manag. 2019 Aug 1;15:965-977.
45. ICH. ICH Harmonised Tripartite Guideline E5(R1): Ethnic factors in the acceptability of foreign 
clinical data. 5 February 1998.
46. European Parliament and Council of the European Union. Regulation (EU) 016/679: Protection of 
natural persons with regard to the processing of personal data and on the free movement of such 
data, and repealing Directive 95/46/EC (General Data Protection Regulation). April 2016. 
Official Journal of the European Union L119, May 2016.
47. Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and 
pregnancy testing in clinical trials. 15 September 2014. 
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48. Lipton RB, Micieli G, Russel G, Solomon S, Tfelt-Hanse P, Waldenlind E. The IHS Members’ 
Handbook 1997/98: Guidelines for controlled trials of drugs in cluster headache. First edition: 
International Headache Society Committee on Clinical Trials in Cluster Headache.
49. Crawford B, Burgess S, Burell A, Tellefsen C. Development and validation of the sleep impact 
scale for insomnia. Value in Health, 2007;10:A304. 
50. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of Life 
Research. 2011;20:1727–1736.
51. Reilly MC, Zbrozek AS, Dukes, EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics. 1993;4(5):353–365.
52. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia 
Suicide Severity Rating Scale: initial validity and internal consistency findings from three 
multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–1277. 
53. ICH. ICH Harmonised Tripartite Guideline E2A: Clinical safety data management: definitions 
and standards for expedited reporting. October 1994.
54. European Parliament and Council of the European Union. Directive 2001/20/EC: Approximation 
of the laws, regulations and administrative provisions of the Member States relating to the 
implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products 
for human use. 4 April 2001. Official Journal of the European Communities L 121, May 2001.
55. International Committee of Medical Journal Editors (ICMJE). Recommendations for the conduct, 
reporting, editing, and publication of scholarly work in medical journals. [Internet] 
icmje.org/icmje-recommendations.pdf. December 2017.
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Appendix I
Clinical Study Protocol
Authentication and 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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