Clinical trial NCT04152083
Conditions: Migraine
Sponsor: H. Lundbeck A/S
Start date: 2019-11-07; Completion date: 2020-07-08
Enrollment: 485 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of eptinezumab administered intravenously in participants experiencing an acute attack of migraine.

Detailed description:
This will be a parallel group, double-blind, randomized, placebo-controlled study assessing the efficacy of eptinezumab for acute migraine, defined as an active intercurrent migraine occurring in those participants who are candidates for preventive therapy. Participants will be randomized to receive a single dose of eptinezumab or placebo in a 1:1 ratio. The total study duration will be approximately 4 to 12 weeks, including up to an 8-week screening period and 4-week of safety follow-up, with clinic visits occurring on Screening, Day 0 (dosing day), and Week 4.

Arms: arm 1: Participants will receive a single dose of eptinezumab 100 milligrams (mg) administered via intravenous (IV) infusion on Day 0. arm 2: Participants will receive a single dose of placebo matching to eptinezumab administered via IV infusion on Day 0.
Interventions: intervention 1: Eptinezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Injection for IV administration intervention 2: Injection for IV administration

Protocol documents:
Prot_000.pdf: 
Protocol ALD403-CLIN-015   
Lundbeck Seattle BioPharmaceuticals, Inc. 
01-Jul-2020 
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CONFIDENTIAL 
Page 1 of 65 
 
LUNDBECK SEATTLE BIOPHARMACEUTICALS, INC. 
Clinical Study Protocol 
 
 
 
 
Confidential Information 
The confidential information in this document is provided to you as an Investigator, potential 
Investigator, or Consultant, for review by you, your staff, and applicable institutional review committees. 
This information will not be disclosed to others without written authorization from Lundbeck Seattle 
BioPharmaceuticals, Inc., except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered. 
Clinical Study Title 
A Parallel Group, Double-Blind, Randomized, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
Eptinezumab Administered Intravenously in Subjects 
Experiencing an Acute Attack of Migraine 
Protocol Number 
ALD403-CLIN-015 
Study Drug 
Eptinezumab 
Indication 
Relief from an active migraine, in patients who are 
candidates for preventive migraine therapy 
Sponsor 
Lundbeck Seattle BioPharmaceuticals, Inc. 
11804 North Creek Pkwy S 
Bothell, WA 98011 USA 
Phone: +1 425-205-2900 
Fax: +1 425-205-2901 
Sponsor’s Medical Monitor 
 
Lundbeck Seattle BioPharmaceuticals, Inc. 
 
 
Clinical Study Compliance 
This clinical study will be conducted in accordance with 
standards of Good Clinical Practice, as defined by the 
International Conference on Harmonisation and all 
applicable federal and local regulations. 
IND Number  
114647 
Date of Protocol (original release) 
Date of Amendment I 
Date of Amendment II  
Date of Amendment III 
27-Mar-2019 
02-Oct-2019 
06-Dec-2019 
01-Jul-2020 


Protocol ALD403-CLIN-015   
Lundbeck Seattle BioPharmaceuticls, Inc. 
 
SIGNATURE PAGE 
 
Declaration of Sponsor 
Title:  A Parallel Group, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Eptinezumab Administered Intravenously in Subjects Experiencing an 
Acute Attack of Migraine 
This clinical trial protocol was subject to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the Study Drug, with moral ethical and 
scientific principles governing clinical research, and in accordance with Good Clinical Practice 
and applicable federal and local regulations. 
 
 
 
______
_________________ 
_____________________ 
 
 
 
 
 
 
   Date   
 
Lundbeck Seattle BioPharmaceuticals, Inc. 
7/1/2020


Protocol ALD403-CLIN-015  
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DECLARATION OF THE PRINCIPAL INVESTIGATOR 
 
Title: A Parallel Group, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the 
Efficacy and Safety of Eptinezumab Administered Intravenously in Subjects Experiencing an 
Acute Attack of Migraine 
I confirm that I have read the above-mentioned protocol and its attachments.  I agree to conduct 
the described trial in compliance with stipulations of the protocol, regulations and ICH E6 
Guideline for Good Clinical Practice (GCP).  
 
Principal Investigator  
 
 
_____________________________________ 
______________________ 
Signature 
Date 
_____________________________________ 
 
Name (printed) 
 
_____________________________________ 
 
Title 
 
_____________________________________ 
 
Institution 
 
 
 


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1. 
PROTOCOL SYNOPSIS 
Title 
A Parallel Group, Double-Blind, Randomized, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
Eptinezumab Administered Intravenously in Subjects 
Experiencing an Acute Attack of Migraine 
Sponsor 
Lundbeck Seattle BioPharmaceuticals, Inc. 
Study Phase 
Phase 3B 
Study Drug, Dose and 
Schedule 
A single administration of eptinezumab, a humanized anti-
calcitonin gene-related peptide (CGRP) monoclonal antibody, 
100 mg or placebo provided by intravenous infusion. 
Primary Objective 
To evaluate the effect of eptinezumab compared to placebo with 
respect to time to headache pain freedom AND time to absence 
of most bothersome symptom during an intercurrent migraine 
that occurs in subjects who are candidates for preventive 
therapy.   
 
Secondary Objectives 
To evaluate the efficacy of eptinezumab vs. placebo on: 
• Headache pain freedom at timepoints up to 48 hours 
• Absence of most bothersome symptom at timepoints up to 
48 hours 
• Time to headache pain relief 
• Sustained headache pain freedom from 2 – 48 hours 
• Acute rescue medication use 
• Effect on symptoms of the qualifying migraine 
• Effect on patient-reported outcomes 
Methodology 
This will be a parallel group, double-blind, randomized, placebo-
controlled study assessing the efficacy of eptinezumab for acute 
migraine, as defined as an active intercurrent migraine occurring 
in those patients who are candidates for preventive therapy. 
Subjects will be randomized to receive either 100 mg 
eptinezumab or placebo in a 1:1 ratio. Randomization will be 
stratified by concomitant migraine preventive treatment and 
region. The total study duration will be approximately 4 to 12 
weeks, including up to 8-week screening period, with clinic visits 
occurring on Screening, Day 0 (dosing day), and Week 4. 
Weekly site/subject contact attempts via a mobile application or 
phone call will occur between screening and Day 0. The number 
of weekly contacts will be based on the length of time from the 
Screening visit to Day 0. Randomization and dosing will be 
triggered by a qualifying migraine and will occur on Day 0. 
Study design requires that study drug administration be initiated 


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within 1 to 6 hours of migraine onset, and subjects must be 
willing and able to travel to the site for study drug administration 
within this time frame. Subjects must remain at the site for 
4-hours post start-of-infusion for observation. Subjects may be 
followed longer than 4 weeks, if necessary, for safety follow-up 
as described in the protocol. An eDiary will be assigned prior to 
dosing at the Day 0 visit and dosed subjects must complete the 
eDiary at the prescribed intervals through 48 hours after start of 
infusion (t=0). Additionally, subjects will complete eDiary data 
entry from Day 3 until a new migraine is reported. 
 
Number of Subjects 
Planned 
Approximately 450 subjects will be randomized and dosed at up 
to 100 sites. 
Subject Selection Criteria 
Male or female subjects between 18 and 75 years of age, 
inclusive, who were diagnosed with migraine at < 50 years of 
age, have a history of migraine for > 1 year before screening and 
a frequency of 4 – 15 migraine days per month in the 3 months 
prior to screening. By history, the subject’s typical migraine 
attack, if untreated, would be associated with headache pain of 
moderate to severe intensity and a most bothersome symptom of 
nausea, photophobia, or phonophobia.  Subjects must be 
headache free for at least 24 hours prior to onset of a qualifying 
migraine. 
Duration of Treatment 
This is a single-dose study with a 4-week follow-up period. 
Duration of Clinical Study 
Participation 
4 – 12 weeks  
Clinical Study Endpoints 
• Co-Primary Endpoints: 
o Time to headache pain freedom 
o Time to absence of most bothersome symptom 
• Key Secondary Endpoints: 
o Headache pain freedom at 2 hours 
o Absence of most bothersome symptom at 2 hours 
• Secondary Endpoints 
o Absence of headache pain at 4 hours 
o Absence of most bothersome symptom at 4 hours 
o Use of rescue medication within the first 24 hours 
• Exploratory Endpoints 
o Time to headache pain relief 
o Headache pain freedom at 2 hours with sustained 
headache pain freedom for 24 and 48 hours 
o Use of rescue medication within the first 48 hours 


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o Absence of photophobia at all timepoints 
o Absence of phonophobia at all timepoints 
o Absence of nausea at all timepoints 
o Change from Baseline in Headache Impact Test 
(HIT-6) at Week 4 
o Change from Baseline in Migraine Treatment 
Optimization Questionnaire-6 (mTOQ-6) at 
Week 4 
o Absence of headache pain at all timepoints other 
than 2 and 4 hours 
o Patient Global Impression of Change (PGIC) at 
Week 4 
o Time to next migraine 
o Time to first rescue medication 
• Safety Endpoints 
o Adverse events (AEs) and serious adverse events 
(SAEs) 
o Clinical laboratory assessments 
o Vital signs 
o Electrocardiograms (ECGs)   
o Columbia-Suicide Severity Rating Scale 
(C-SSRS) 
 
Concomitant Medications 
Anti-CGRP treatments are prohibited for the duration of the 
study. 
Medications which are not prohibited are allowed during the 
study.  
The following medications must be avoided for at least 
24 hours prior to study drug administration and 2 hours after 
start of study drug administration: 
• Triptans, ergotamines and ergot-derivatives  
• Analgesics (including but not limited to 
acetaminophen, tramadol, nonsteroidal anti-
inflammatory drugs [NSAIDs], combination 
analgesics, caffeine-containing analgesics and 
opioids/narcotics) and other acute migraine 
medication(s)  
• Antiemetic medications (including but not limited to 
prochlorperazine, promethazine, droperidol, 
chlorpromazine, metoclopramide) 


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• Antihistamines (except if required to treat allergic 
reactions) 
• Devices, neuromodulation, neurostimulation, or 
injectable therapy (trigger point injections, 
extracranial nerve blocks, facet joint injections, spinal 
manipulation)  
Any form of magnesium or cannabis-based products intended for 
the acute treatment of the qualifying migraine (Day 0) is 
prohibited until 2 hours after study drug administration. 
Botulinum toxin for migraine or for any other medical/cosmetic 
reasons is prohibited for the 7 days prior to study drug 
administration through 48 hours after study drug administration. 
Systemic corticosteroids for migraine or any other reason are 
prohibited for the 3 months prior to study drug administration 
through 48 hours after study drug administration except if 
required to treat life threatening allergic reactions. 
Rescue medication, defined as any medication to treat migraine 
or migraine associated symptoms, can be provided to the subject 
any time after 2 hours post start of infusion.  
Any migraine preventive treatment use must be stable and 
ongoing for at least 1 month prior to screening and for the 
duration of the study. 


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Sample Size 
The planned sample size for this study is 450 randomized and 
dosed subjects. These subjects will be allocated into 2 treatment 
groups, eptinezumab vs. placebo, in a 1:1 ratio.  
 
Two hundred twenty-five subjects per group provides at least 
90% power to detect a 0.736 hazard ratio favoring eptinezumab 
at the 5% significance level for both co-primary endpoints. In 
addition, this sample size also provides 90% power for the key 
secondary endpoints, assuming that each at 5% significance level 
eptinezumab increases response rates for both 2-hour endpoints 
by at least 14.5 percentage points and that the correlation 
between these two endpoints is 0.8. 
 
Statistical Analysis 
For each of the co-primary time-to-event endpoints, the 
difference between groups with respect to time to pain freedom 
or time to absence of MBS will be tested using a Cox 
proportional hazards model at the 5% significance level. For each 
of the key secondary 2-hour endpoints, the treatment groups will 
be compared using a Cochran-Mantel-Haenszel test (CMH), 
adjusting for the study’s stratification factor. The key secondary 
endpoints will be tested hierarchically at a 5% significance level 
(pain freedom at 2 hours, followed by absence of most 
bothersome symptom at 2 hours). For each of the secondary 
endpoints, the treatment groups will be compared the same way 
as for the key secondary endpoints. If both key secondary 
endpoints achieve statistical significance, the secondary 
endpoints will be tested hierarchically at 5% level of significance 
(pain freedom at 4 hours, followed by absence of most 
bothersome symptom at 4 hours, followed by use of rescue 
medication within 24 hours).     
 


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2. 
 SCHEDULE OF EVENTS AND ASSESSMENTS  
Table 1: 
Schedule of Events and Assessments 
 
Assessment 
Screening Period 
(Day -56 to Day -1) 
Rand/ 
Dosing Day 
End of Study/Early Term  
(Day 28 ± 3) 
Screening Visit 
Weekly Contact 7 
Day 0 Visit 
Week 4 Visit 
Informed Consent  
X 
 
 
 
Inclusion/Exclusion Criteria1 
X 
 
X 
 
Demographics 
X 
 
 
 
Medical History (including family and social history) 
X 
 
 
 
Height, Weight and BMI2 
X 
 
X 
X 
Physical Exam 
X 
 
 
X 
Vital Signs3 
X 
 
X 
X 
eDiary Training1 
X 
 
X 
 
eDiary Completion4 
 
 
X 
 
Migraine History 
X 
 
 
 
Qualifying Migraine Assessment1 
 
 
X 
 
HIT-6 
X  
 
 
X 
mTOQ-6 
X 
 
 
X 
PGIC 
 
 
 
X 
C-SSRS5 
X 
X 
 
X 
12-lead ECG 
X 
 
 
X 
Hematology/Chemistry1 
X 
 
X 
X 
Serology (HIV/Hepatitis B and C) 
X 
 
 
 
Urine Drug Screen1 
X 
 
X 
 
Urine Pregnancy (hCG) Test1 
X 
 
X 
X 
AE Review1,6 
X 
X 
X 
X 
Concomitant Medication Review1,6 
X 
X 
X 
X 
Randomization1 
 
 
X 
 
Eptinezumab/placebo administration 
 
 
X 
 
Please refer to next page for footnotes. 
 
 
 
 
 
 
 
 


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1 Prior to dosing on Dosing Day 
2Height and BMI only collected at Screening visit. Weight collected at Screening, Day 0 and Week 4 visits.  
3 On Day 0, vital signs should be collected pre-dose and any time prior to the subject leaving the site post-dose. 
4 An electronic diary (eDiary) will be assigned before dosing on the Day 0 visit to collect migraine data pre-dose through 48 hours. Additionally, subjects will 
complete eDiary data entry from Day 3 until a new migraine is reported.  
5 C-SSRS “Baseline/Screening Version” should be used at the screening visit and C-SSRS “Since Last Visit Version” should be used at all subsequent 
timepoints. Complete C-SSRS at Screening, Week 4 and, if applicable, the weekly contact after the subject has been in screening for 4 weeks. If the screening 
period exceeds 28 days, the C-SSRS “Since Last Visit Version” should be completed via a phone call to the subject on Screening Day 29 (+7 days). 
6 If the screening period exceeds 28 days, AEs and concomitant medications should be reviewed via a phone call to the subject on Screening Day 29 (+7 days).  
7 Weekly contact attempts will occur in which updates are obtained from the subject via a mobile application or a phone call from the site staff to check in with 
the subject during the screening period. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 2: 
Schedule of Events and Assessments for Day 0 through 48 Hours  
 
 
Assessment 
Pre-dose 
Dose 
 
 
Post Start of Infusion 
 
 
 
Start of 
Infusion 
0.5 hr 
(+20 
min) 
1 hr 
(+20 
min) 
1.5 hr 
(+20 
min) 
2 hr 
(+20 
mins 
2.5 hr 
(+20 
min) 
3 hr 
(+20 
min) 
3.5 hr 
(+20 
mins) 
4 hr 
(+2 
hr) 
6 hr 
(+3 
hr) 
9 hr 
(+3 
hr) 
12 hr 
(+12 
hr) 
24 hr 
(+12 
hr) 
48 hr 
(+12 
hr) 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eDiary Training 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
eDiary Completion1 
X 
 
X3 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Qualifying Migraine 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs2 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
Hematology/Chemistry 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine Pregnancy (hCG) 
Test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse Event Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication 
Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eptinezumab/placebo 
administration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 An electronic diary (eDiary) will be assigned before dosing on the Day 0 visit to collect migraine data. eDiary will be completed by the subject. While the 
subject is in the clinic the study staff will provide close oversight to ensure subject completes eDiary at all timepoints, as close to the beginning of the window as 
possible. 
2 On Day 0, vital signs should be collected pre-dose and any time prior to the subject leaving the site post-dose. 
3 Immediately when the infusion is started, the subject will be required to press a button on the eDiary device to indicate that the infusion has started. 
Note: Timepoint windows only pertain to subject completion of eDiary.


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3. 
LIST OF ABBREVIATIONS 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AED 
Automated external defibrillator 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase   
ANCOVA 
AST 
Analysis of Covariance 
Aspartate aminotransferase  
BMI 
Body Mass Index 
BP 
Blood pressure 
CGRP 
Calcitonin Gene-Related Peptide  
CMH 
Cochran-Mantel-Haenszel  
CRF 
Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
eDiary 
Electronic Diary 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIT-6 
Headache Impact Test 
IB 
Investigator’s Brochure 
ICD 
International Classification of Diseases 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ICHD 
International Classification of Headache Disorders 
IHS 
International Headache Society 
IgG1 
Immunoglobulin G1 
IRB 
Institutional Review Board 
IV 
Intravenous 
IRT 
Interactive Response Technology 
mAb 
Monoclonal antibody 
MBS 
Most Bothersome Symptom 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOH 
Medication Overuse Headache 
MTOQ-6 
Migraine Treatment Optimization Questionnaire-6 
NSAID 
Non-steroidal anti-inflammatory drug 


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PGIC 
Patient Global Impression of Change  
RBC 
Red blood cell 
SAE 
Serious adverse event 
TMD 
Temporomandibular Disorder 
TVS 
Trigeminovascular System 
WBC 
White blood cell 


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4. 
TABLE OF CONTENTS 
SIGNATURE PAGE .......................................................................................................................2 
DECLARATION OF THE PRINCIPAL INVESTIGATOR ..........................................................3 
1. 
PROTOCOL SYNOPSIS .............................................................................................4 
2. 
SCHEDULE OF EVENTS AND ASSESSMENTS.....................................................9 
3. 
LIST OF ABBREVIATIONS.....................................................................................12 
4. 
TABLE OF CONTENTS ...........................................................................................14 
5. 
INTRODUCTION ......................................................................................................19 
5.1. 
Background .................................................................................................................19 
5.2. 
Eptinezumab Background Information .......................................................................20 
5.2.1. 
Summary of Clinical Studies ......................................................................................20 
5.2.2. 
Dose Justification ........................................................................................................21 
5.3. 
Risks and Benefits ......................................................................................................21 
5.4. 
Compliance Statement ................................................................................................22 
6. 
OBJECTIVES .............................................................................................................23 
6.1. 
Primary Objective .......................................................................................................23 
6.2. 
Secondary Objectives .................................................................................................23 
7. 
STUDY DESIGN .......................................................................................................24 
7.1. 
Clinical Study Endpoints ............................................................................................24 
7.1.1. 
Co-Primary Efficacy Endpoints ..................................................................................24 
7.1.2. 
Key Secondary Endpoints: .........................................................................................24 
7.1.3. 
Secondary Endpoints ..................................................................................................24 
7.1.4. 
Exploratory Endpoints ................................................................................................24 
7.1.5. 
Safety Endpoints .........................................................................................................25 
7.2. 
Clinical Study Design .................................................................................................25 
7.3. 
Methods to Minimize/Avoid Bias ..............................................................................25 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................26 
8.1. 
Inclusion Criteria ........................................................................................................26 
8.2. 
Exclusion Criteria .......................................................................................................27 
8.3. 
Registration and Treatment Assignment ....................................................................29 
8.3.1. 
Registration Procedure, Subject Numbering ..............................................................29 
8.3.2. 
Randomization and Treatment Assignment ................................................................29 


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8.4. 
Subject Early Withdrawal ...........................................................................................30 
8.4.1. 
Criteria for Withdrawal from the Clinical Study ........................................................30 
8.4.2. 
Timing of Withdrawal ................................................................................................30 
8.4.3. 
Follow-up for Early Withdrawal ................................................................................30 
8.4.4. 
Replacement Policy ....................................................................................................30 
8.4.5. 
Lost to Follow-Up.......................................................................................................30 
9. 
STUDY DRUG ...........................................................................................................31 
9.1. 
Eptinezumab ...............................................................................................................31 
9.2. 
Placebo ........................................................................................................................31 
9.3. 
Study Drug Dosing and Administration .....................................................................31 
9.3.1. 
Packaging and Labeling ..............................................................................................31 
9.3.2. 
Blinding ......................................................................................................................32 
9.3.3. 
Storage and Handling of Study Drug ..........................................................................32 
9.3.4. 
Accountability and Disposition of Investigational Product ........................................32 
9.3.5. 
Disposition of Study Drug ..........................................................................................32 
9.4. 
Concomitant Medications ...........................................................................................33 
9.4.1. 
Prohibited Medications/Treatments ............................................................................33 
9.4.2. 
Restricted Medications/Treatments ............................................................................33 
9.4.3. 
Rescue Medications ....................................................................................................34 
9.4.4. 
Contraceptives ............................................................................................................34 
10. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................35 
10.1. 
Schedule of Assessments ............................................................................................35 
10.2. 
Assessments and Procedures ......................................................................................35 
10.2.1. 
Eligibility Verification ................................................................................................35 
10.2.2. 
Randomization and Dosing .........................................................................................35 
10.2.3. 
Demographics .............................................................................................................35 
10.2.4. 
Medical and Migraine History ....................................................................................35 
10.2.5. 
Physical Examinations ................................................................................................36 
10.2.6. 
Vital Signs ..................................................................................................................36 
10.2.7. 
eDiary Assessments ....................................................................................................36 
10.2.8. 
Qualifying Migraine Assessment ...............................................................................37 
10.2.9. 
Questionnaires ............................................................................................................37 
10.2.10. 
12-Lead ECG ..............................................................................................................38 


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10.2.11. 
Laboratory Samples and Testing ................................................................................38 
11. 
ASSESSMENT OF SAFETY .....................................................................................40 
11.1. 
Adverse Events ...........................................................................................................40 
11.1.1. 
Definitions ..................................................................................................................40 
11.1.2. 
Assessment of Adverse Events ...................................................................................40 
11.1.3. 
Recording Adverse Events .........................................................................................42 
11.1.4. 
Reporting Serious Adverse Events .............................................................................43 
11.1.5. 
Unexpected and Related Serious Adverse Events ......................................................43 
11.1.6. 
Follow-up of Adverse Events .....................................................................................44 
11.1.7. 
Pregnancy ...................................................................................................................44 
11.1.8. 
Suicidal Ideation and Behavior ...................................................................................44 
11.2. 
Management of Reactions to Study Drug ...................................................................45 
12. 
ASSESSMENT OF EFFICACY ................................................................................46 
12.1. 
Headache Pain Freedom .............................................................................................46 
12.2. 
Most Bothersome Migraine-Associated Symptom .....................................................46 
12.3. 
Sustained Pain Freedom .............................................................................................46 
12.4. 
Rescue Medication ......................................................................................................46 
13. 
STATISTICAL CONSIDERATIONS .......................................................................47 
13.1. 
Decision Rule ..............................................................................................................47 
13.2. 
Sample Size ................................................................................................................47 
13.3. 
General Considerations ...............................................................................................47 
13.3.1. 
Definition of Baseline .................................................................................................47 
13.3.2. 
Handling of Missing Data ...........................................................................................47 
13.3.3. 
Populations to be Analyzed ........................................................................................47 
13.4. 
Statistical Methods ......................................................................................................48 
13.4.1. 
Subject Disposition, Demographics and Baseline Characteristics .............................48 
13.4.2. 
Efficacy Analyses .......................................................................................................48 
13.4.3. 
Safety Analyses ..........................................................................................................49 
14. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS .....................................50 
14.1. 
Data Quality Assurance ..............................................................................................50 
14.2. 
Case Report Forms and Source Documents ...............................................................50 
14.3. 
Study Documentation .................................................................................................50 
14.4. 
Data Collection and Electronic Data Capture (EDC) .................................................50 


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14.5. 
Archiving Clinical Trial Records ................................................................................50 
14.6. 
Good Clinical Practice ................................................................................................51 
14.7. 
Informed Consent .......................................................................................................51 
14.8. 
Protocol Approval and Amendment ...........................................................................52 
14.8.1. 
Premature Termination of the Clinical Study .............................................................52 
14.9. 
Confidentiality ............................................................................................................52 
14.10. 
Publication Policy .......................................................................................................53 
15. 
APPENDICES ............................................................................................................54 
15.1. 
Migraine preventive therapies with established or probable efficacy 
(Esternalik, 2013), (Antonaci, 2010), (Pringsheim, 2012) .........................................54 
15.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Risk Assessment ......................56 
15.2.1. 
Baseline/Screening Version ........................................................................................56 
15.2.2. 
Since Last Visit Version .............................................................................................59 
15.3. 
Migraine Treatment Optimization Questionnaire- 6 (MTOQ-6) ................................62 
15.4. 
Patient Global Impression of Change (PGIC) ............................................................63 
15.5. 
Headache Impact Test (HIT-6 v1.0) ...........................................................................64 
16. 
REFERENCES ...........................................................................................................65 


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LIST OF TABLES 
Table 1: 
Schedule of Events and Assessments ...........................................................................9 
Table 2: 
Schedule of Events and Assessments for Day 0 through 48 Hours ............................11 
Table 3: 
Eptinezumab Clinical Studies .....................................................................................21 
 


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5. 
INTRODUCTION  
5.1. 
Background 
Migraine is a highly prevalent paroxysmal neurological disease characterized by recurrent 
episodes of moderate to severe headache associated with physiological disruptions of 
neurological, gastrointestinal, and sensory function.  Attacks of migraine typically last between 
4 and 72 hours, produce significant disability, and recur often without warning, over decades of 
time.  Migraine is more common in women and most prevalent through the 3rd and 4th decades 
of life, amplifying its impact on family and career development (Lipton, 2007). Migraine is one 
of the most prevalent neurological disease for which medical treatment is sought, and worldwide, 
is considered the leading cause of disability for people under the age of 50 and 2nd leading cause 
of disability worldwide (Leonardi, 2005). Annually, lost work time and diminished productivity 
attributable to migraine costs American employers an estimated $19.6 billion (Stewart, 2003). 
Generally, migraine begins as an episodic disease.  Between attacks of migraine, the nervous 
system returns to a normal (premorbid) state of function.  However, approximately 2.5% of 
people with episodic migraine will annually transform from episodic to chronic migraine, 
meaning they are experiencing migraine on greater than 15 days per month for at least 
3 consecutive months (Headache Classification Committee, 2018). For those with chronic 
migraine, the headaches are more intense; associated with more migraine-associated symptoms, 
and there is greater disease-related impact and disability and in general there is a failure to return 
to normal (pre-morbid) neurological function between episodes of headache (Katsarava, 2012). 
The pathophysiology of migraine is complex and incompletely understood.  Current models of 
migraine are based on a genetically determined hyper-excitable nervous system characterized by 
a lowered threshold to sensory activation and uniqueness in sensory processing (Durham, 2004). 
Interactions between the migraine nervous system and specific internal and external stimuli 
(migraine triggers) can result in activation of the trigeminovascular system (TVS).  Once 
activated, the TVS releases various vasoactive peptides generating peripheral sensitization of 
trigeminal and upper cervical nociceptors. The ensuing peripheral nociceptive stimuli synapsing 
in the Trigeminal Nucleus Caudalis ultimately lead to a state of central sensitization as third 
order neurons in the thalamus become sensitized (Cady, 2012). Clinically, during a fully 
developed attack of migraine, central sensitization can be observed as sensory allodynia.   
Central to this model of migraine pathophysiology is calcitonin gene-related peptide (CGRP).  
CGRP is one of the most abundant peptides in the human body and is produced in both 
peripheral and central neurons.  It is abundantly stored in trigeminal afferents and when released 
during migraine leads to vasodilation, the release of inflammatory peptides, and increased 
sensory transmission.  In both peripheral and central pain pathways, CGRP is associated with 
pain transmission and neuronal sensitization (Durham, 2006). Intravenous (IV) infusions of 
CGRP can cause a migraine-like headache in susceptible individuals with migraine (Hansen, 
2010). In addition, many pharmacological agents used as acute or prophylactic treatment of 
migraine are known to inhibit CGRP.  Thus, CGRP is an attractive target for development of 
novel migraine pharmacology. 
The pharmacological treatment of migraine can be divided into two categories: one is to reverse 
or abort an attack of migraine after it is initiated and the second class is to protect the nervous 


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system from generating future migraines.  Preventive treatments generally do not abort a 
migraine that has already began.   
Intercurrent migraine is defined as an active migraine that occurs in a patient population that are 
candidates for preventive therapy. While intercurrent migraine is not explicitly defined by the 
IHS, medications for active migraine such as triptans have been previously been studied 
(MacGregor, 2009).   While generally quite effective, excessive use of acute treatments for 
active migraine can actually worsen the severity and frequency of migraine causing a secondary 
headache condition called medication overuse headache (MOH) (Headache Classification 
Committee, 2018). MOH is common in populations with chronic migraine (Schmid, 2013). 
Thus, it is critical to initiate preventive treatment before medication overuse is established.   
5.2. 
Eptinezumab Background Information 
A significant unmet treatment need for subjects with migraine is for an effective treatment that 
can abort an existing migraine and at the same time prevent future migraine from occurring.  
Eptinezumab is currently being reviewed by the Food and Drug Administration (FDA) for an 
indication in migraine prevention.  Unique to its profile is that it is administered as an 
intravenous infusion and throughout its Phase 2 and Phase 3 development programs, it has 
consistently demonstrated preventive efficacy as soon as the first day following infusion.  This 
raises the possibility that eptinezumab has the potential to be a treatment intervention for active 
migraine and at the same time, provide a sustained preventive benefit. In a key secondary 
endpoint for the percentage of patients with a migraine after dosing, there was a statistically 
significant reduction in Day 1 migraine frequency for both the 100 and 300 mg groups relative to 
placebo in ALD403-CLIN-011; in ALD403-CLIN-006, the results were not significant after 
multiplicity adjustments.  
Eptinezumab is a genetically engineered humanized immunoglobulin G1 (IgG1) antibody that 
binds to human-α-CGRP with an affinity of 1.5E-11 M and human-β-CGRP with an affinity of 
5.7E-11 M. Eptinezumab is being developed by Lundbeck Seattle BioPharmaceuticals, Inc. 
(Lundbeck Seattle) for the prevention of migraine.  However, as an intravenous infusion (IV) 
with 100% bioavailability, a T-max of 30 minutes, rapid engagement and high affinity for 
CGRP, eptinezumab may also be suitable as a treatment for active migraine. 
5.2.1. 
Summary of Clinical Studies 
Detailed descriptions of the relevant clinical findings for eptinezumab are provided in the 
Investigator’s Brochure (IB). 
A summary of the migraine studies completed and ongoing eptinezumab clinical studies is 
shown in Table 3.  


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Table 3: 
Eptinezumab Clinical Studies 
Study ID 
Phase/Objective 
Study Subject 
Population 
Total 
Number of 
Subjects in 
the Study 
Number of 
Subjects 
Randomized 
and Dosed with 
Eptinezumab 
Number of 
Subjects 
Randomized 
and Dosed 
with 
Placebo 
ALD403-CLIN-002 
(completed) 
Phase 1b 
Safety & 
Efficacy 
Frequent 
Episodic 
Migraine 
163 
81 
82 
ALD403-CLIN-005 
(completed) 
Phase 2 
Safety & 
Efficacy 
Chronic Migraine 
616 
495 
121 
ALD403-CLIN-006 
(completed) 
Phase 3 
Safety & 
Efficacy 
Frequent 
Episodic 
Migraine 
888 
666 
222 
ALD403-CLIN-011 
(completed) 
Phase 3 
Safety & 
Efficacy 
Chronic Migraine 
1072 
706 
366 
ALD403-CLIN-013 
(completed) 
Phase 3 
Safety, Open 
Label 
Chronic Migraine 
128 
128 
No Placebo 
  
5.2.2. 
Dose Justification 
Since the objective of this study is to assess treatment of active migraine in patients who require 
preventive therapy, 100 mg is deemed to be the lowest effective dose. This is based on the 
ALD403-CLIN-006 and ALD403-CLIN-011 studies in prevention, where 100 mg dose group 
provided benefit as early as Day 1 and conferred efficacy out to Week 12.   
5.3. 
Risks and Benefits 
Eptinezumab may be effective as a treatment for active migraine as well as providing preventive 
benefit for 12 weeks.    
There may be unknown adverse effects and unforeseeable risks associated with study drug 
administration or unexpected interactions with another drug that have not yet been identified.  
As with all protein therapeutics, there is a risk of both non-serious and serious allergic reactions.  
Please refer to the Investigator Brochure (IB) for additional details.  


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In the completed eptinezumab clinical studies, the most common adverse reaction in ≥ 2% of 
treated patients and ≥ 2% of placebo patients was nasopharyngitis.  The majority of these adverse 
events were categorized as mild to moderate. 
The safety of eptinezumab has been evaluated in 2,076 patients with migraine who received at 
least one dose of eptinezumab, representing 1615 patient-years of exposure. Long term data with 
eptinezumab is limited; however, 128 subjects have been treated with up to 2 years of exposure.  
• Healthy volunteer studies have included limited dosing, with follow-up limited to 
3-4 months post last dose.  
• Studies in migraine subjects have also included up to 20 weeks of follow-up for 
Safety. No new significant adverse safety findings were noted during the follow-up 
period. 
• An open label long term follow-up safety study included no new significant findings 
identified during the long-term follow-up period. 
The safety findings to date indicate that eptinezumab is well tolerated and demonstrates a 
favorable risk-benefit profile based on review of nonclinical, clinical, and scientific literature 
data. 
5.4. 
Compliance Statement 
This clinical study will be conducted in accordance with standards of Good Clinical Practice 
(GCP) as defined by the International Conference on Harmonisation (ICH) and all applicable 
federal and local regulations. 


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6. 
OBJECTIVES 
6.1. 
Primary Objective 
The primary objective is: 
To evaluate the effect of eptinezumab compared to placebo with respect to time to headache 
pain freedom AND time to absence of most bothersome symptom during an intercurrent 
migraine that occurs in subjects who are candidates for preventive therapy.   
6.2. 
Secondary Objectives 
The secondary objectives are to evaluate the efficacy of eptinezumab vs. placebo on: 
• Headache pain freedom  
• Absence of most bothersome symptom 
• Time to headache pain relief 
• Sustained headache pain freedom from 2 – 48 hours 
• Acute rescue medication use 
• Effect on symptoms of the qualifying migraine 
• Effect on patient-reported outcomes 


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7. 
STUDY DESIGN 
7.1. 
Clinical Study Endpoints 
Detail regarding the clinical study endpoints and their derivation can be found in Section 12. 
Migraine headaches are defined as migraines as outlined in the International Headache Society 
(IHS) International Classification of Headache Disorders (ICHD, 3rd edition, version 2018), 
Section 1.3 (Headache Classification Committee, 2018).  
7.1.1. 
Co-Primary Efficacy Endpoints 
• Time to headache pain freedom 
• Time to absence of most bothersome symptom 
7.1.2. 
Key Secondary Endpoints: 
• Headache pain freedom at 2 hours   
• Absence of most bothersome symptom at 2 hours 
7.1.3. 
Secondary Endpoints 
• Absence of headache pain at 4 hours 
• Absence of most bothersome symptom at 4 hours 
• Use of rescue medication within the first 24 hours 
7.1.4. 
Exploratory Endpoints 
• Time to headache pain relief 
• Headache pain freedom at 2 hours with sustained headache pain freedom for 24 and 
48 hours 
• Use of rescue medication within the first 48 hours 
• Absence of photophobia at all timepoints 
• Absence of phonophobia at all timepoints 
• Absence of nausea at all timepoints 
• Change from Baseline in Headache Impact Test (HIT-6) at Week 4 
• Change from Baseline in Migraine Treatment Optimization Questionnaire-6 (mTOQ-
6) at Week 4 
• Absence of headache pain at all timepoints other than 2 and 4 hours 
• Patient Global Impression of Change (PGIC) at Week 4 
• Time to next migraine 
• Time to first rescue medication 


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7.1.5. 
Safety Endpoints 
• Adverse events (AEs) and serious adverse events (SAEs) 
• Clinical laboratory assessments 
• Vital signs 
• Electrocardiograms (ECGs)   
• Columbia-Suicide Severity Rating Scale (C-SSRS) 
7.2. 
Clinical Study Design 
This will be a parallel group, double-blind, randomized, placebo-controlled study assessing the 
efficacy of eptinezumab for acute migraine. Acute migraine for this study will be defined as an 
active intercurrent migraine occurring in those patients who are candidates for preventive 
therapy. Subjects will be randomized to receive either 100 mg eptinezumab or placebo in a 
1:1 ratio. Randomization will be stratified by concomitant migraine preventive treatment and 
region.  
The total study duration will be approximately 4 to 12 weeks, including up to 8-week screening 
period, with clinic visits occurring on Screening, Day 0 (dosing day), and Week 4. Weekly 
site/subject contact attempts via a mobile application or phone call will occur between screening 
and Day 0. The number of weekly contacts will be based on the length of time from the 
Screening visit to Day 0. Randomization and dosing will be triggered by a qualifying migraine 
and will occur on Day 0. Study design requires that study drug administration be initiated within 
1 to 6 hours of migraine onset, and subjects must be willing and able to travel to the site for 
study drug administration within this time frame. Subjects must remain at the site for 4-hours 
post start-of-infusion for observation. Subjects may be followed longer than 4 weeks, if 
necessary, for safety follow-up as described in the protocol. An eDiary will be assigned prior to 
dosing at the Day 0 visit and dosed subjects must complete the eDiary at the prescribed intervals 
through 48 hours after start of infusion (t=0). Additionally, subjects will complete eDiary data 
entry from Day 3 until a new migraine is reported. 
Approximately 450 subjects will be randomized and treated. Efficacy and safety assessments 
will be conducted according to the Schedule of Events and Assessments presented in Section 2.    
7.3. 
Methods to Minimize/Avoid Bias 
To minimize bias, this clinical study is randomized, double-blinded, and placebo controlled.   


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8. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
8.1. 
Inclusion Criteria 
A subject must meet all of the following criteria during the screening period and on Day 0 to be 
eligible for inclusion in the study:  
1. Male or female subjects 18 – 75 years of age, inclusive, at time of informed consent. 
2. Willing and able to read, understand, and sign the Informed Consent Form (ICF) for the 
clinical study approved by the investigator’s local Review Board or a central Institutional 
Review Board (IRB) or Ethics Committee (EC). 
3. Has adequate venous access for administration of study drug and collection of blood 
samples. 
4. Greater than 1-year history of migraine, with or without aura, with onset of first migraine 
before age 50 as defined by ICHD-3. 
5. Migraine on 4 – 15 days per month in the 3 months prior to screening. 
6. By history, the subject’s typical migraine attacks, if untreated, are associated with 
headache pain of moderate to severe intensity and a most bothersome symptom of 
nausea, photophobia, or phonophobia.  These migraine attacks must be a minimum 
duration of 4 hours and maximum duration of 72 hours. 
7. History of either previous or active use of triptans for migraine. 
8. Headache free for at least 24 hours prior to onset of a qualifying migraine. 
9. On Day 0, subjects must have a moderate to severe headache associated with at least one 
of the following headache characteristics: pulsating quality, unilaterality, and aggravation 
by or avoidance of routine physical activity.  In addition, they must have during the 
headache at least one of the following: 
a. Nausea and/or vomiting 
b. Photophobia and phonophobia 
10. On Day 0, subject must be able to reliably identify the time of qualifying migraine onset. 
11. Able and willing to be dosed with study drug during a qualifying migraine attack within 8 
weeks of screening visit. 
12. Women of child-bearing potential and males with partners of child-bearing potential must 
agree to use adequate contraception for the duration of the study. Adequate contraception 
includes oral, transdermal, or injectable (depot) estrogen and/or progestogen, selective 
estrogen receptor modulator therapy, intrauterine contraceptive device, double barrier 
method (e.g., condom with spermicidal gel or diaphragm with spermicidal gel) or 
vasectomy with use of condom (for male subjects).  Females are considered of 
childbearing potential unless they are permanently sterilized (i.e., bilateral tubal ligation, 
bilateral salpingectomy, bilateral oophorectomy of hysterectomy) at least 3 months prior 
to screening or postmenopausal (i.e., no menses for 1 year).  


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13. Any hormonal therapy (e.g., contraceptives, hormone replacement therapy) use is stable 
and ongoing for at least 3 months prior to screening and through up to treatment with 
study drug (Day 0). 
14. Willing, committed, and able to comply with scheduled clinic visits and complete all 
study-related procedures. 
15. Subject agrees not to post any personal medical data or information related to the study 
on any website or social media site (e.g., Facebook, Twitter). 
16. Subject is willing to complete the eDiary from Day 0 through the 48-hour period after 
dosing and from Day 3 until a new migraine is reported.   
17. Subject is willing and able to have study drug administration within 1-6 hours of onset of 
a qualifying migraine and remain at the site for 4 hours post start of infusion for 
observation. 
8.2. 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Unable to differentiate migraine from other headache or pain disorders.  
2. Use of the following medication, for any indication, within the 24-hour period prior to 
dosing with study drug: 
a. Triptans, ergotamines and ergot-derivatives  
b. Analgesics (including but not limited to acetaminophen, tramadol, nonsteroidal anti-
inflammatory drugs [NSAIDs], combination analgesics, caffeine-containing 
analgesics and opioids/narcotics) and other acute migraine medication(s)  
c. Antiemetic medications (including but not limited to prochlorperazine, promethazine, 
droperidol, chlorpromazine, metoclopramide) 
d. Antihistamines 
e. Devices, neuromodulation, neurostimulation, or injectable therapy (trigger point 
injections, extracranial nerve blocks, facet joint injections, spinal manipulation)  
3. On Day 0, use of magnesium or cannabis-based products intended for acute treatment of 
the qualifying migraine. 
4. History of new daily persistent headache in any of the 3 months prior to screening.  
5. History or diagnosis of chronic tension-type headache, hypnic headache, cluster 
headache, hemicrania continua, new daily persistent headache, or unusual migraine 
subtypes such as hemiplegic migraine (sporadic and familial), ophthalmoplegic migraine 
and migraine with neurological accompaniments that are not typical of migraine aura 
(e.g., diplopia, altered consciousness, or long duration). 
6. History or diagnosis of vestibular migraine.  
7. Any changes to preventive migraine treatment(s) within 1 month prior to screening and 
up to treatment with study drug (Day 0).  
8. Use of the following medication, for any indication, in each of the 3 months prior to 
screening: 


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a. opioids/narcotics or butalbital containing products (including combinations) on more 
than 4 days per month; OR 
b. triptans, ergotamines, or combination analgesics for 10 or more days per month; OR 
c. acetaminophen, aspirin or nonsteroidal anti-inflammatory drugs [NSAIDs] for 15 or 
more days per month (except if subject is taking 81 mg dose of aspirin for cardiac 
prophylaxis) 
9. Any use of approved devices, neuromodulation, neurostimulation or injectable therapy 
(trigger point injections, extracranial nerve blocks, facet joint injections) within the 
24-hour period prior to treatment with study drug (Day 0). 
10. Any use of botulinum toxin for migraine or for any other medical/cosmetic reasons 
requiring injections within 7 days prior treatment with study drug (Day 0). 
11. Any use of systemic corticosteroid for migraine or any other reason within 3 months prior 
to treatment with study drug (Day 0). 
12. Evidence or medical history of clinically significant psychiatric diseases that are 
uncontrolled and/or untreated.  
13. Clinically significant laboratory findings showing evidence of organ dysfunction, any 
clinically significant deviation from the normal range (abnormal tests may be repeated for 
confirmation at the discretion of the investigator), or clinically significant physical exam 
abnormalities at screening, as evaluated by the investigator.  
14. Have present or previous malignancies, except: 
• Squamous or basal skin cell carcinoma with excision without evidence of recurrence 
• Malignancy ≥ 5 years since diagnosis/treatment without evidence of recurrence 
15. Known history or evidence of hereditary fructose intolerance, severe atopy, or life-
threatening allergy (e.g. anaphylaxis). If questions arise, the investigator should contact 
the medical monitor for guidance.   
16. Any clinically significant, concurrent medical condition on the day of infusion.  
17. Clinically significant abnormal ECG during the screening period. 
18. Positive human immunodeficiency virus (HIV), Hepatitis B surface antigen (HBsAg), 
and/or Hepatitis C antibody (HCV) at screening. 
19. Body Mass Index (BMI) > 35 kg/m2 at screening. 
20. Primary or secondary hypertension that is uncontrolled.  Note: Mild primary hypertension 
that is well-controlled for ≥ 6 months prior to screening is allowed. 
21. The subject is at risk of self-harm or harm to others in the investigator’s opinion, based 
on clinical interview and responses provided on the Columbia-Suicide Severity Rating 
Scale (C-SSRS).  Subjects must be excluded if they have a lifetime history of a serious 
suicide attempt or multiple suicide attempts (i.e., actual, interrupted, or aborted attempts), 
have had any suicidal behavior in the past 5 years (i.e., preparatory acts or behavior), or 
have had suicidal ideation of Type 3, 4, or 5 (i.e., suicidal ideation with any method 
without intent to act or suicidal ideation with intent to act, with or without a plan) in the 


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past 6 months, as measured by the C-SSRS at Screening visit or phone contact during 
screening period.   
22. Any history or evidence of substance abuse or dependence (e.g., alcohol, opiates, 
amphetamines and barbiturates) within the past 2 years according to the International 
Classification of Diseases (ICD) 10: F10-19. 
23. Pregnant, breastfeeding, or planning to become pregnant during the study. 
24. Receipt of any experimental, unregistered therapy (within or outside a clinical study) 
within 30 days or 5 plasma half-lives (whichever is longer) prior to screening. Note: 
Subject use of rimegepant and ubrogepant are allowed to screen provided they have 
discontinued the drug at a total of 5 half-lives. 
25. Receipt of any monoclonal antibody treatment, for migraine or any other indication, 
(within or outside a clinical study) within 6 months prior to screening. 
26. Planned or current participation in any other interventional clinical study during the 
duration of this clinical study, or within 1 month prior to screening. 
27. Any condition that, in the opinion of the investigator, would make the subject unsuitable 
for the clinical study including but not limited to clinically unstable cardiovascular 
disease, arteriosclerosis, cardiomyopathy, coronary artery disease, serious heart rhythm 
abnormalities, neurological disease, cerebrovascular disease, diabetes, Raynaud’s disease. 
28. Employees of the Sponsor, Clinical Research Organization, or any clinical study site 
involved in this study and their immediate family members (i.e., parents, spouse, siblings, 
children). 
8.3. 
Registration and Treatment Assignment 
8.3.1. 
Registration Procedure, Subject Numbering 
Each participating investigative site will be assigned a 3-digit site number (e.g., 601, 602). At the 
screening visit, once the subject signs the ICF they are registered in the electronic data capture 
(EDC), which will assign a unique subject number. The first three digits of the subject number 
identify the site, and the remaining four digits identify the subject. 
Subjects who fail screening may be rescreened if approved in advance by the medical monitor.   
8.3.2. 
Randomization and Treatment Assignment 
Randomization and dosing must occur at the dosing visit (Day 0) as specified in the schedule of 
events and once the eligibility assessments are approved by the medical monitor.  
Sites will complete randomization in EDC, and the randomization assignment will be obtained 
by the clinical study site’s unblinded pharmacist or designee in an interactive web/voice 
randomization system (IxRS).  Subjects will be randomized in a 1:1 ratio to one of the treatment 
groups.  Randomization will be stratified by concomitant migraine preventive treatment 
(concomitant migraine preventive treatment use vs. no concomitant migraine preventive 
treatment use) and region (North America vs. Rest of World). 


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Randomized subjects who terminate their clinical study participation for any reason, regardless 
of whether study drug was administered or not, will retain their randomization assignment and 
subject number.  
8.4. 
Subject Early Withdrawal 
Subjects may withdraw from the clinical study at any time and for any reason without penalty or 
prejudice to his or her future medical care.   
8.4.1. 
Criteria for Withdrawal from the Clinical Study 
Subjects will be withdrawn from the clinical study for any of the following reasons: 
• Withdrawal of consent for the collection of clinical study data including further 
access to medical records. The reason for withdrawal of consent will be recorded. 
• Termination of the study by the sponsor 
• Investigator decision (with medical monitor approval) 
• Lost to follow-up 
The reason for withdrawal and the date of withdrawal must be recorded on the case report form 
(CRF). 
8.4.2. 
Timing of Withdrawal 
Subjects are considered withdrawn from the clinical study at the time that any of the criteria 
listed in Section 8.4.1 are met and the last study assessment is performed, or at the time of the 
early termination visit, whichever occurs later. 
8.4.3. 
Follow-up for Early Withdrawal 
Subjects who wish to withdraw their consent from study participation will be asked to have an 
early termination visit with associated visit assessments (see Schedule of Events and 
Assessments in Section 2).  Subjects who withdraw consent before or after randomization but do 
not receive study drug may discontinue the study without any further procedures. 
8.4.4. 
Replacement Policy 
Subjects who are withdrawn from the clinical study after randomization will not be replaced.   
8.4.5. 
Lost to Follow-Up 
If the subject fails to attend scheduled study visits or to respond to requests for follow-up, the 
clinical study site will send a registered letter, at a minimum, to the subject requesting contact 
with the clinic.  All attempts to resume contact (including copies of written correspondence and 
documentation of telephone and email contact attempts) will be included in the source 
documentation.  Subjects who do not respond to requests for follow-up after all reasonable 
attempts to establish contact will be considered lost to follow-up. 


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9. 
STUDY DRUG 
9.1. 
Eptinezumab 
Eptinezumab is an anti-calcitonin gene-related peptide humanized monoclonal antibody (anti-
CGRP mAb) that is being developed by Lundbeck Seattle BioPharmaceuticals, Inc., for the 
preventive treatment of migraine. As an intravenous infusion (IV) with 100% bioavailability, a 
Tmax of 30 minutes, rapid engagement and high affinity for CGRP, Lundbeck Seattle believes it 
may be suited for treatment of an active [intercurrent] migraine. 
Eptinezumab injection, 100 mg/mL (1 mL per vial), is presented in USP/Ph Eur. Type 1 glass 
vials as a single-use preservative-free solution for IV administration.  Eptinezumab is formulated 
at a concentration of 100 mg/mL with a pH of 5.8.  Those subjects randomized to the 
eptinezumab treatment group will receive an IV infusion of eptinezumab injection in 100 mL of 
0.9% saline.   
9.2. 
Placebo 
Placebo will be supplied as a single-use preservative-free solution in a 2-mL Type I glass vial 
formulated with the same excipients as eptinezumab, without the active ingredient. Those 
subjects randomized to placebo will receive an IV infusion of placebo in 100 mL of 0.9% saline. 
9.3. 
Study Drug Dosing and Administration 
The pharmacist or designee is responsible for receiving, storing and preparing study drug and 
placebo, as well as transferring study drug or placebo to the blinded staff for administration.  
Unblinded staff will not be responsible for other aspects of the clinical study where blinding is 
necessary. Both randomization and dosing must occur on Day 0. Doses of eptinezumab or 
placebo (total volume of 100 mL) will be administered intravenously over a period of 30 (+15) 
minutes on Day 0 by the blinded investigator or designee.  
The study drug administration must be initiated within 1 to 6 hours of onset of the qualifying 
migraine. Subjects must remain at the site and be monitored by site staff for at least 4 hours post-
dose.  The investigator must be immediately available during the infusion and for at least 4 hours 
post start of infusion to assess each subject for the occurrence of adverse events.  Subjects will be 
requested to stay longer than 4 hours after dosing should the investigator determine this is 
clinically warranted (e.g., subjects should be observed until all AEs are resolved or clinically 
stable).  The timeframe for the post-dose observation period must be documented in the source 
record. 
Further instructions on preparation and procedures associated with administering the IV can be 
found in the Pharmacy Manual and Infusion Guidelines. 
9.3.1. 
Packaging and Labeling 
Before the shipment to the sites, study drug will be labeled with information (protocol number, 
contents, concentration, storage instructions and any other information), required by regulatory 
agencies and a statement that it is limited to investigational use. Study drug to be administered to 
the subject will be labeled after dose preparation by the unblinded pharmacist or designee as 
specified in the Pharmacy Manual in a manner that protects the blind. 


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9.3.2. 
Blinding 
This clinical study is double-blinded, meaning the subjects, investigator and site personnel are 
blinded to treatment assignment, except for the site’s unblinded pharmacist or designee. The site 
must have a written plan in place, site blinding plan, to ensure blinding is adequately maintained 
for the study.  If the blind is broken, the date, time, and reason must be recorded in the source. 
The blind should only be broken for reasons in which knowledge of the treatment assignment is 
critical to the management of subject safety. Medical monitor approval should be obtained prior 
to breaking the blind if possible. The principal investigator will report any cases of unblinding to 
the Sponsor within 24 hours of the incident. Please refer to the site blinding plan and the infusion 
guidelines for additional details regarding breaking the study blind. 
9.3.3. 
Storage and Handling of Study Drug 
Eptinezumab will be stored at the site at 2°C to 8°C in accordance with any accompanying 
instructions.  
Placebo will be stored at the site at -20°C (-10°C to -25°C) in accordance with any accompanying 
instructions.   
Please refer to the Pharmacy Manual for additional storage and handling procedures.  Diluent 
(0.9% saline) will be stored according to manufacturer instructions. 
Investigators shall take adequate precautions, including storage of eptinezumab and placebo in a 
securely locked, substantially constructed cabinet or other securely locked, substantially 
constructed enclosure, access to which is limited to maintain blind, prevent theft or diversion of 
the substance into illegal channels of distribution. 
9.3.4. 
Accountability and Disposition of Investigational Product 
The investigator is responsible for maintaining accurate study drug accountability records 
throughout the clinical study. The site must maintain a Study Drug Accountability Log, on which 
the unblinded pharmacist or designee will record the receipt, lot number, quantity and 
dispensation of study drug. Please refer to the Pharmacy Manual for additional details regarding 
study drug accountability.  
Where more than one secure area is being used for storage at a site, all movement of study drug 
through the chain of custody must be recorded in accountability records such that full 
reconciliation may be completed at the end of the study.  
Included with each study drug shipment is a form listing lot numbers and quantity shipped. The 
unblinded pharmacist or designee will acknowledge receipt and integrity of these supplies.  A 
copy will be retained in the site's pharmacy binder during study conduct. 
9.3.5. 
Disposition of Study Drug 
After completion of the clinical study, the investigator is responsible for either returning or 
destroying all unused study drug. The investigator must verify that no remaining supplies are in 
his/her possession. All used/partially used vials/IV bags will be destroyed onsite according to the 
site SOPs or returned according to Lundbeck Seattle directive. Destruction must be in 
accordance with local regulations for the product type.   


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If the clinical study is terminated, suspended, discontinued, or completed, the investigator or 
designee shall return the unused supplies to the sponsor or designee, or otherwise provide for 
disposition of the unused supplies (as authorized by the sponsor).  
9.4. 
Concomitant Medications 
Any concomitant therapy used from the time the subject signs the informed consent form 
through study completion must be recorded on the CRF, including medications required for 
treatment of any AEs or SAEs. The medication name, dosage, date, and indication for use must 
be recorded. The medical monitor or designee should be notified in advance of (or as soon as 
possible after) any instances in which restricted therapies are administered.  
9.4.1. 
Prohibited Medications/Treatments 
Anti-CGRP treatments are prohibited for the duration of the study. 
9.4.2. 
Restricted Medications/Treatments 
Medications which are not prohibited specifically are allowed during the study.  
The following medications must be avoided for 2 hours after start of study drug 
administration: 
• Triptans, ergotamines and ergot-derivatives  
• Analgesics (including but not limited to acetaminophen, tramadol, nonsteroidal anti-
inflammatory drugs [NSAIDs], combination analgesics, caffeine-containing 
analgesics and opioids/narcotics) and other acute migraine medication(s)  
• Antiemetic medications (including but not limited to prochlorperazine, promethazine, 
droperidol, chlorpromazine, metoclopramide) 
• Antihistamines (except if required to treat allergic reactions) 
• Any form of magnesium or cannabis-based products  
• Devices, neuromodulation, neurostimulation, or injectable therapy (trigger point 
injections, extracranial nerve blocks, facet joint injections, spinal manipulation)  
Botulinum toxin for migraine or any other medical/cosmetic reasons is prohibited for the 48 
hours after start of study drug administration. 
Systemic corticosteroids for migraine or for any other reason are prohibited for 48 hours after 
start of study drug administration except if required to treat life threatening allergic reactions. 
Any hormonal therapy (e.g., contraceptives, hormone replacement therapy) use must be stable 
and ongoing for at least 3 months prior to screening and for the duration of the study.  
Any migraine preventive treatment use must be stable and ongoing for at least 1 month prior to 
screening and for the duration of the study. 
At the discretion of the investigator, on a case by case basis, changes to the treatment regimen 
that might be clinically warranted may be made prior to Week 4 after consulting with the 
medical monitor and obtaining approval. 


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Sites are required to indicate if a medication is used for prophylaxis purposes or if it is used for 
the acute treatment of migraines. The investigator should re-evaluate the subject’s risk factors 
relative to the prescribing information for both prophylactic and acute treatments that the subject 
is using, and judge that the use of these medications continues to be considered safe. 
The Medical Monitor should be contacted for any questions regarding restricted medications. 
9.4.3. 
Rescue Medications 
Rescue medication is defined as any medication to treat migraine or migraine associated 
symptoms. Two hours after start of study drug administration, subjects who did not adequately 
respond may take their own rescue medication or may elect to take no further medication. 
Inadequate response is defined as meeting 1 of the following: 
• Continues to experience moderate or severe headache pain; OR 
• Continues to experience significant migraine associated symptoms; OR 
• After initial migraine relief at 2 hours, headache or migraine associated symptoms 
returns within 2 to 48 hours after the dose of study drug 
At the discretion of the investigator, additional rescue medication may be provided to the subject 
2 hours post start of infusion if their own rescue medication is inappropriate or does not provide 
adequate relief. Common examples of rescue medications include ketorolac, injectable or 
intranasal triptans, antiemetics, diphenhydramine, or in extreme cases, opioids. 
9.4.4. 
Contraceptives 
All women are required to have a negative pregnancy test at the Screening Visit and on Day 0 
prior to dosing. Women of child-bearing potential and males with partners of child-bearing 
potential must agree to use adequate contraception during the screening period of the study and 
for the duration of the study. Abstinence is not an acceptable form of contraception for this 
study. Acceptable methods of contraception for females of child-bearing potential and males 
with partners of child-bearing potential are: 
• Intrauterine devices  
• Double-barrier methods (e.g., condoms and/or diaphragms/cervical cap with 
spermicidal gel or foam) 
• Hormonal contraceptives (oral, depot, patch, injectable, intrauterine devices or 
vaginal ring), stabilized for at least 3 months prior to screening 
• Vasectomy with use of condom (for male subjects) 
Females are considered of childbearing potential unless they are: 
• Permanently sterilized (i.e., bilateral tubal ligation, bilateral salpingectomy, bilateral 
oophorectomy or hysterectomy) at least 3 months prior to screening 
• Postmenopausal (i.e., no menses for at least 1 year) 


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10. 
STUDY ASSESSMENTS AND PROCEDURES 
10.1. 
Schedule of Assessments 
Assessment and procedures at each visit are summarized in Section 2 - Schedule of Events and 
Assessments.  
10.2. 
Assessments and Procedures 
10.2.1. 
Eligibility Verification 
During subject screening, after the ICF is signed and subject is determined by the site to be 
eligible, the site will submit an Eligibility Verification Packet to the PRA Medical Monitor via 
the Clinical6 portal, see the Clinical6 training materials for additional information.  
10.2.2. 
Randomization and Dosing 
Randomization and dosing must occur at the Day 0 visit, once the medical monitor approves the 
subject’s eligibility status.   
All subjects will be randomized via EDC after the following:   
• Eligibility has been approved by the medical monitor 
• Review of all inclusion/exclusion criteria to confirm subject is eligible on Day 0 
• Subject confirms continued interest in participating in the study 
If > 6 hours has passed since the onset of migraine, the subject will not be dosed with study drug.  
10.2.3. 
Demographics 
The year of birth, age, sex, ethnicity and race, will be collected in the source and recorded and in 
the CRF at Screening.   
10.2.4. 
Medical and Migraine History 
Medical history collection will include medical history as well as social and family history.  
Significant historic and current medical conditions or illnesses, allergies to medications, and 
prior surgical interventions will be recorded in the source records and in the CRF.  Symptoms 
present at the time of informed consent will be considered medical history.   
Migraine history will be collected at the screening visit by the investigator. The data gathered 
will be collected in the source and recorded in the CRF, including but not limited to:  
• Diagnostic criteria for migraine with or without aura as defined by ICHD-3 
• Migraine medication use (past and present, acute and preventive) 
• Age at diagnosis of migraine, migraine triggers and other details of the subjects’ history 
with migraine 
Investigators must demonstrate due diligence in obtaining medical records.  All attempts to 
obtain medical records should be documented.  If medical records cannot be obtained, history 


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may be confirmed via subject interview in order to obtain sufficient information to confirm all 
eligibility criteria are met. 
10.2.5. 
Physical Examinations 
Physical examinations will be performed at the times noted in the Schedule of Events and 
Assessments in Section 2 and must be performed by an investigator who has been trained and 
delegated the task on the Delegation of Authority Log. 
The physical examination at the screening visit will be comprehensive and appropriate to 
determine the overall physical health of each subject. Examination of the genitourinary system 
and rectum may be deferred by the investigator if the subject’s related medical history and 
review of systems are negative.  For all other visits that call for a physical examination, the body 
systems examined will be at the discretion of the investigator.   
Physical examinations will also include height, weight and BMI, which can be delegated to other 
blinded site staff. Weight will be measured at all visits, while height and BMI will be measured 
at screening only. 
Abnormal physical examination findings at the screening visit will be recorded as medical 
history.  Any new or worsening physical examination finding identified at subsequent visits will 
be considered an AE.   
10.2.6. 
Vital Signs 
Vital signs, including blood pressure (BP) and heart rate, will be measured at the time points 
specified in the Schedule of Events and Assessments in Section 2. 
When measuring vital signs, the subject should be rested for 5 minutes before obtaining vital 
signs.  Blood pressure may be repeated to confirm measurement if appropriate.    
10.2.7. 
eDiary Assessments 
Subjects will be assigned an electronic diary (eDiary) prior to dosing on Day 0 to collect 
migraine data. At the Screening and Day 0 visits, the site staff will train the subject on eDiary 
use and educate the subject on the importance of completing the eDiary at all timepoints. 
Subjects will be instructed to complete the eDiary at all timepoints from pre-dose through 
48 hours. Additionally, subjects will complete eDiary data entry from Day 3 until a new 
migraine is reported (specified in the Schedule of Events and Assessments [Section 2]). The 
subject will be instructed to return the eDiary at the Week 4 clinic visit. The data collected 
includes but is not limited to: 
• Start of infusion (t=0) 
• Headache severity on a four-point Likert scale (0=none, 1=mild, 2=moderate, 
3=severe) 
• Presence or absence of migraine associated symptoms, including nausea, photophobia 
or phonophobia, one of which will be identified prior to dosing as the subject's most 
bothersome migraine-associated symptom 
• Use of rescue and acute treatment of migraine medication  


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10.2.8. 
 Qualifying Migraine Assessment 
The Qualifying Migraine Assessment will be completed at the Day 0 visit prior to randomization 
by an investigator. The data gathered by this questionnaire includes but is not limited to: 
• Headache characteristics 
• Symptoms of the migraine the subject is currently experiencing to confirm qualifying 
migraine.  
o Note: Presenting migraine symptoms on the day of study drug administration are 
not considered adverse events and will be collected and monitored separately. 
• Time of migraine onset 
10.2.9. 
Questionnaires 
Protocol number, subject number and date of administration must be captured on all 
questionnaires.   
10.2.9.1. Headache Impact Test (HIT-6) 
The Headache Impact Test (HIT-6) is a tool used to measure the impact and effect on the ability 
to function normal in daily life when a headache occurs. The HIT-6 is a 6 question, Likert-type, 
self-reporting questionnaire with responses ranging from “Never” to “Always” with the 
following response scores: Never=6, Rarely=8, Sometimes=10, Very Often=11, Always=13. The 
total score for the HIT-6 is the sum of each response score and will be treated as missing if the 
response is missing for one or more questions. The HIT-6 total score ranges from 36 to 78, with 
score ranges having the following life impact: 
 
Subjects will be given the questionnaire at Screening and Week 4 visits and asked to review the 
brief instructions and complete. The completed HIT-6 questionnaire must be reviewed for 
completeness and clarity by site staff prior to the subject leaving the clinic.  The subject should 
be asked to complete any unanswered questions. 
10.2.9.2. Migraine Treatment Optimization Questionnaire-6 (mTOQ-6) 
The migraine treatment optimization questionnaire-6 (mTOQ-6) is a tool used to assess response 
to acute treatment in persons with migraine. The mTOQ-6 is a 6 question, Likert-type, self-
reporting questionnaire with responses ranging from “Never” to “Half The Time Or More” with 
the following response scores: Never=1, Rarely=2, Less Than Half The Time=3, Half The Time 
Or More=4. The total score for the mTOQ-6 is the sum of each response score and will be 
treated as missing if the response is missing for one or more questions.  
Subjects will be given the questionnaire at Screening and Week 4 visits and asked to review the 
brief instructions and complete. The completed mTOQ-6 questionnaire must be reviewed for 


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completeness and clarity by site staff prior to the subject leaving the clinic.  The subject should 
be asked to complete any unanswered questions. 
10.2.9.3. Patient Global Impression of Change (PGIC) 
The PGIC includes a single question concerning the subject’s impression of the change in their 
disease status since the start of the study. Seven responses are possible: Very Much Improved, 
Much Improved, Minimally Improved, No Change, Minimally Worse, Much Worse, Very Much 
Worse.  
Subjects will be given the questionnaire at the Week 4 visit and asked to review the brief 
instructions and complete. The completed PGIC questionnaire must be reviewed for 
completeness and clarity by site staff prior to the subject leaving the clinic.   
10.2.9.4. Columbia-Suicide Severity Rating Scale (C-SSRS)  
The Columbia–Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates 
suicidal ideation and behavior. The C-SSRS will be administered by trained (i.e., C-SSRS 
certified) site staff at the time points specified in the Schedule of Events and Assessments in 
Section 2.  The C-SSRS “Baseline/Screening” version will be used for the Screening Visit, and 
the C-SSRS “Since Last Visit” version will be used for all subsequent visits. 
10.2.10. 
12-Lead ECG 
ECGs will be performed using a 12-lead ECG device provided for the study at the time points 
specified in the Schedule of Events and Assessments in Section 2. ECG data will be transmitted 
and read centrally by a cardiologist; however, the investigator must review the ECG at screening 
and Week 4 and ensure there are no clinically significant abnormalities. In addition, all 
confirmed (i.e., centrally-read) ECGs will be reviewed by the investigator and evaluated for 
clinical significance to verify eligibility.   
All ECGs are expected to be performed on the ECG device provided to the site by the study 
sponsor. A local ECG device may be used only if there are technical issues with the central ECG 
device that cannot be resolved while the subject is onsite. If a local ECG device is used, a paper 
ECG must be submitted to the central ECG reader. All technical issues must be reported 
immediately to the central ECG help desk. 
10.2.11. 
Laboratory Samples and Testing 
10.2.11.1. Urine Drug Screening 
A screening test for drugs of abuse will be performed on urine samples during the screening visit 
and on Day 0 visit prior to dosing.  Urine drug screen kits will be provided by the central lab and 
the test performed on site.  If a urine drug screen is positive and there is no medical record 
documentation of prescribed medications to explain the result, the subject should be considered 
for exclusion from the study. Questions regarding the eligibility can be addressed with the 
medical monitor. 


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10.2.11.2. Pregnancy Testing 
Urine pregnancy tests will be performed for all female subjects, regardless of childbearing 
potential, at the specified time points in the Schedule of Events and Assessments, Section 2.  
Urine pregnancy test must be performed and reviewed prior to randomization and dosing on 
Day 0. 
Urine pregnancy test kits will be provided by the central lab and the test performed on site. 
The contraceptive method used by females of child-bearing potential and males with partners of 
child-bearing potential must be confirmed with the subject and recorded in the source record at 
screening and reconfirmed with the subject and recorded in the source record at each subsequent 
study visit. 
10.2.11.3. Clinical Laboratory Testing 
Blood samples for clinical laboratory tests, including hematology, serum chemistry and serology 
[including human immunodeficiency virus (HIV), Hepatitis B and Hepatitis C], will be collected 
at the time points specified in the Schedule of Events and Assessments in Section 2.   
Serum chemistry tests include albumin, alkaline phosphatase (ALP), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST), urea nitrogen, calcium, bicarbonate, creatinine, 
globulin, glucose, phosphorus, potassium, sodium, total bilirubin, total cholesterol, total protein, 
triglycerides, magnesium and uric acid. 
Hematology tests include hematocrit, hemoglobin, platelet count, red blood cell (RBC) count, 
and white blood cell (WBC) count with differentials (neutrophils, lymphocytes, monocytes, 
eosinophils, and basophils). 
All clinical laboratory blood samples will be initially processed by site staff and shipped to a 
central laboratory for analysis as specified in the Laboratory Manual.  A licensed medical 
provider listed on the Form FDA 1572 will review all lab reports and document clinical 
significance for any out-of-range lab value(s) listed in the report.   


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11. 
ASSESSMENT OF SAFETY  
11.1. 
Adverse Events 
11.1.1. 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
participant administered a pharmaceutical product that does not necessarily have a causal 
relationship with the treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a study drug, whether or not related to the study drug. (ICH E6) 
11.1.2. 
Assessment of Adverse Events 
The investigator is required to monitor the occurrence of adverse events for each subject from 
the time of informed consent through the course of the clinical study.  Adverse events may be 
reported by the subject, reported by a caregiver, or reported by the investigative site through 
investigator site personnel open-ended questioning, through physical examination, laboratory 
test, documentation in medical records, or by other means.  Adverse events include: 
• Any new undesirable medical experience or an unfavorable and unintended change of 
an existing condition that occurs during or after treatment, whether or not considered 
related to the study drug. 
• Any abnormal assessment or laboratory findings considered by the investigator to be 
clinically significant.  Clinically significant findings include but are not limited to 
those that lead to discontinuation or interruption of study treatment, require 
therapeutic intervention, or require a change in subject management. 
A new or 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 recorded on the AE CRF. A pre-
existing or chronic condition that worsens after signing the informed consent is considered an 
adverse event.  
Pre-existing medical conditions of clinical significance must be included in the subject’s medical 
history and recorded on the medical history CRF page. Presenting migraine symptoms on the day 
of study drug administration are not considered adverse events. 
Progression of treatment indication including new or worsening of anticipated clinical signs or 
symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the symptom progression and /or lack of efficacy, should NOT be reported as 
adverse events unless the symptom progression is greater than anticipated in the natural course of 
the disease. 
Each event recorded on the AE CRF is required to be assessed by the investigator with regard to 
the following; seriousness, severity, and relationship to study drug, as outlined below. 


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Lack of Efficacy or Worsening of Migraines 
Events that are clearly consistent with the expected pattern of progression of the underlying 
migraine should NOT be recorded as AEs. Migraine activity will be recorded in the eDiary and 
these data will be captured as effectiveness assessment data only. If there is any uncertainty as to 
whether an event is due to disease progression or worsening, it should be reported as an AE. 
Seriousness 
An adverse event or suspected adverse event is considered serious if in the view of either the 
investigator or sponsor, it results in; 
• Death 
• Is life-threatening (that the subject is at risk of death at the time of the event; it does 
not mean that the event hypothetically might have caused death if it were more 
severe) 
• Inpatient hospitalization or prolonged existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions.  
• Congenital anomaly/ birth defect 
• Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgement, they may jeopardize the patient or subject and/or may require medical or 
surgical intervention to prevent one of the outcomes listed in the definition (21 CFR 
312.32(a) and ICH E2A). 
Of note: 
• A social hospitalization (i.e., hospitalizations for pre-admissions not due to an acute 
medical issue) is not considered an SAE 
• A hospitalization is defined as greater than 24-hour post hospital admission 
Severity 
The severity of an AE will be graded as follows: 
• Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
• Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL). 
• Grade 3 Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL. 
• Grade 4 Life-threatening consequences; urgent intervention indicated. 
• Grade 5 Death related to AE. 


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Relationship to Study Drug 
The investigator is required to assess the causality/relationship between each AE and the study 
drug as not related or related and record the assessment on the source documents and in the CRF 
AE page. Medical judgment should be used to determine the likely relationship of the AE to the 
study drug considering all relevant factors including (but not limited to) relevant history, 
concomitant medical condition and concomitant medications.  Determination should be based on 
assessment of temporal relationships, biologic plausibility, association (or lack of association) 
with underlying disease, and presence (or absence) of a more likely cause.   
Not Related: It is plausible that the AE has an etiology other than the study drug (e.g., pre-
existing condition, underlying disease, concomitant medical condition, or concomitant 
medication). 
Related: The AE cannot reasonably be explained by the subject’s clinical state, concomitant 
medical condition or concomitant therapies, and a temporal relationship exists between the 
event onset and administration of the study drug.  
11.1.3. 
Recording Adverse Events 
Event reporting will extend from time of informed consent until completion of the final visit. 
AEs should be recorded on the AE CRF, whether believed by the investigator to be related or not 
related to the study drug.  
AE reporting should contain: 
• A brief description of the event 
• Date of onset  
• Date of resolution 
• Severity 
• Actions taken or treatment required  
• Relationship to study drug  
• Outcome  
• Whether the event is considered serious 
Whenever possible, the investigator should group signs or symptoms that constitute a single 
diagnosis into a single event term.  For example, “cough, rhinitis, and sneezing” might be 
grouped together as “upper respiratory tract infection.” 
Asymptomatic abnormal findings considered by the investigator to be clinically significant 
should be recorded as an AE, unless it is associated with a clinical syndrome that has already 
been reported as an AE.  


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11.1.4. 
Reporting Serious Adverse Events 
All SAEs that occur during the study period (beginning with informed consent), whether 
considered to be related to the study drug or not, must be reported within 24 hours of awareness 
or knowledge of the event.  Serious adverse events occurring within 30 days of the end of the 
clinical study must be reported regardless of the relationship with the study drug. The SAE 
Notification Form should be used to report any related SAEs which occur after the end of the 
clinical study.  
The date the site personnel became aware of the serious adverse event must be recorded in the 
source document.  To report the SAE, complete the CRF AE page and indicate the reason for 
seriousness.  The minimum information required for an initial report is: 
• Sender of report (name, address of investigator) 
• Subject identification (screening/randomization number, initials, NOT subject name) 
• Protocol number 
• Description of SAE (e.g., event term) 
• Seriousness criteria 
• Relationship assessment 
After receipt of the initial report, the medical monitor or designee will review the information 
and, if necessary, contact the investigator to obtain further information for assessment of the 
event.  The Sponsor or designee will be responsible for information processing and reporting in 
accordance with applicable local and regulatory requirements.  
The sponsor will determine if an SAE requires expedited reporting to regulatory agencies.  The 
clinical study site personnel are responsible for reporting these events to their IRB according to 
the institution’s IRB reporting requirements and in accordance with applicable local and 
regulatory requirements. 
Should the EDC System not be available, serious adverse events must be reported on the paper 
SAE Notification Form. Additional details can be found in the Site Manual.  This does not 
replace the EDC reporting system; information must be entered in the EDC system once the 
system returns to normal function. 
11.1.5. 
Unexpected and Related Serious Adverse Events 
Unexpected SAEs are those which: 
• Are not previously reported as associated with eptinezumab, as referenced in the 
Investigator’s Brochure. 
• May be symptomatically and pathophysiologically related to an AE listed in the 
Investigator’s Brochure, but differ from the event due to greater severity, frequency 
or specificity. 
The sponsor or designee will report, to the appropriate regulatory authorities according to local 
and regulatory requirements, unexpected SAEs which are considered related to eptinezumab 
(suspected unexpected serious adverse reactions [SUSARs]).  The clinical study site personnel 


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are responsible for reporting these events to their EC/IRB in accordance with applicable local 
and regulatory requirements. 
11.1.6. 
Follow-up of Adverse Events 
Irrespective of the suspected causality, AEs will be monitored until resolution, stabilization in 
the judgment of the investigator, or the subject completes the study, is lost to follow up or 
withdraws from the study. 
The investigators must report new significant follow-up information to the Sponsor within 24 
hours of becoming aware of the event for SAE’s and enter into EDC Rave within 5 business days 
for AE’s.  New significant information includes the following: 
• new signs or symptoms or a change in the diagnosis 
• significant new diagnostic test results 
• change in causality based on new information 
• change in the event's outcome, including recovery 
• additional narrative information on the clinical course of the event 
11.1.7. 
Pregnancy 
In the event that a female subject becomes pregnant following administration of study drug or 
may have been pregnant at the time of study drug exposure, or the partner of a male subject 
becomes pregnant following administration of study drug, the pregnancy must be reported to the 
sponsor within five business days of the Investigator becoming aware of the pregnancy.  
Pregnancy information will be reported to the Sponsor using the Exposure In-Utero Forms in 
EDC.  
Although pregnancy per se is not considered an AE, the outcome of a pregnancy that results in a 
birth defect or congenital anomaly or hospitalization for any reason is considered to be an SAE.  
Every attempt should be made to follow a pregnancy to conclusion.   
Follow-up information is to be collected by the Investigator and provided to the sponsor 
regarding: 
• The course of the pregnancy including perinatal and neonatal outcome, premature 
termination of the pregnancy, or miscarriage  
• Offspring information including birth weight and birth defects (if any)  
All pregnancies that occur after a subject completes the study and up to 6 months after study 
drug administration should be reported by the subject to the investigative site. The investigator 
must report it to the Sponsor within five business days of awareness or knowledge of the 
pregnancy. 
11.1.8. 
Suicidal Ideation and Behavior  
Recent meta-analyses, spontaneous reports, and published case reports regarding suicidal 
ideation and behavior arising from drugs tested in clinical studies have been noted as an area of 
general concern. Based on this information, the United States Food and Drug Administration 


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(FDA) has provided guidance to prospectively assess suicidal ideation and behavior in clinical 
studies to ensure that subjects in clinical studies who are experiencing suicidal ideation and 
behavior are properly recognized and adequately treated and to ensure the collection of more 
timely and more complete data on suicidal ideation and behavior than have been collected in the 
past (FDA, 2012). The C-SSRS (Columbia-Suicide Severity Rating Scale) will be used for this 
purpose.  Any subject who answers “yes” to questions 4 or 5 of the C-SSRS during the screening 
visit will be referred to a mental health specialist by the investigator.  During the course of the 
study after dosing, any subject who answers “yes” to questions 4 or 5 of the Suicidal Ideation 
section or answers “yes” to any question in the Suicidal Behavior section of the C-SSRS will be 
referred by investigators to a mental health specialist.  Affirmative answers to questions 4 or 5 
for suicidal ideation or to any question for suicidal behavior will be reported in EDC as an AE. 
11.2. 
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.  Emergency equipment and medication for the treatment of these potential adverse 
events must be available for immediate use.   
Should a medical condition arise that the investigator believes is related to the study drug, 
clinical judgment should be used to provide the appropriate response including the consideration 
of discontinuation of study drug. Any events believed to be allergic reactions should be 
discussed with the medical monitor. 
If a subject experiences an allergic reaction, as assessed by the Investigator, that necessitates 
intervention including study drug interruption or discontinuation and/or the administration of 
standard medical treatment, the site will collect additional blood specimens using the immune 
response lab kit, per the laboratory manual, at the time of the event and again at the next 
scheduled visit. This assessment includes serum histamine, serum tryptase, immunoglobulin E, 
and complement components.  


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12. 
ASSESSMENT OF EFFICACY 
The data collected will be used to assess the following endpoints:  
12.1. 
Headache Pain Freedom 
Headache pain will be collected on a 4-point scale with 3 being severe, 2 being moderate, 
1 being mild, and 0 being no pain. Headache pain freedom is defined as no pain (0) with the 
absence of rescue medication (note that rescue medication is prohibited for 2 hours post start of 
infusion). Assessment of headache pain will be taken at all selected timepoints up to 48 hours. 
Time to headache pain freedom, which is one of the co-primary endpoints, is the first timepoint 
post start of infusion at which the subject reports freedom of pain meaning their headache pain 
has gone from moderate or severe (2 or 3) at baseline to no pain (0) with no administration of 
rescue medication. Headache pain freedom at 2 hours post start of infusion is one of the key 
secondary endpoints of this study; evaluation at all other timepoints are secondary (at 4 hours) 
and exploratory endpoints.  
12.2. 
Most Bothersome Migraine-Associated Symptom  
MBS is the symptom (from among nausea, photophobia, or phonophobia) that has been 
identified by the subject on Day 0 prior to dosing as being the most bothersome one for the 
migraine being treated. Absence of MBS is defined as freedom from the migraine-associated 
symptom with no administration of rescue medication. Assessment of MBS will be taken at all 
selected time points from pre-dose to 48 hours. Time to absence of MBS, which is one of the 
co-primary endpoints, is the first timepoint post start of infusion at which the subject reports 
absence of MBS with no administration of rescue medication. Absence of MBS at 2 hours post 
start of infusion is one of the key secondary endpoints of this study; evaluation of absence of 
migraine associated symptoms at all other timepoints are secondary (at 4 hours) and exploratory 
endpoints.  
12.3. 
Sustained Pain Freedom 
Freedom from headache pain (0) at 2 hours and sustaining this pain-free status to 24 and 
48 hours (i.e. pain free 2 - 24 and 2- 48 hours) with no administration of rescue medication. 
12.4. 
Rescue Medication  
Use of rescue medication at any time, which is defined as any intervention (medical or device) 
provided to the subject to provide relief of migraine. This should not be provided sooner than 
2 hours following start of the study drug administration.    
 
 
 


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13. 
STATISTICAL CONSIDERATIONS 
13.1. 
Decision Rule 
Pair-wise testing of each eptinezumab group vs. placebo will be performed. The testing 
procedure will start with primary endpoints. The result that is considered a study success is when 
both time to headache pain freedom and time to absence of MBS are statistically significant at 
the 5% significance level. If this occurs, testing will continue to key secondary endpoints.  
The key secondary endpoints will be tested hierarchically at a 5% significance level (pain 
freedom at 2 hours, followed by absence of most bothersome symptom at 2 hours). If both key 
secondary endpoints achieve statistical significance, the secondary endpoints will be tested 
hierarchically at 5% level of significance (pain freedom at 4 hours, followed by absence of most 
bothersome symptom at 4 hours, followed by use of rescue medication within 24 hours).  
13.2. 
Sample Size 
The planned sample size for this study is 450 randomized and dosed subjects. These subjects will 
be allocated into 2 treatment groups, eptinezumab vs. placebo, in a 1:1 ratio. Two hundred 
twenty-five subjects per group provides at least 90% power to detect a 0.736 hazard ratio 
favoring eptinezumab at the 5% significance level for both co-primary endpoints. In addition, 
this sample size also provides 90% power for the key secondary endpoints, assuming that each at 
5% significance level eptinezumab increases response rates for both 2-hour endpoints by at least 
14.5 percentage points and that the correlation between these two endpoints is 0.8.  
13.3. 
General Considerations 
13.3.1. 
Definition of Baseline 
The baseline assessment will be the latest available valid measurement taken prior to the 
administration of study drug on Day 0 (an eDiary will be assigned before dosing on the day of 
treatment visit).  
13.3.2. 
Handling of Missing Data 
Summary statistics will be reported based upon observed data. Subjects with missing data for the 
time-to-event co-primary endpoints will be considered to be censored at the last timepoint prior 
to the missing assessments. In the case of subjects having missing headache eDiary data at the 
2-hour assessment, they will be assigned as non-responders for the key secondary endpoints, 
regardless of treatment arm.  Additionally, if the start date of an AE or concomitant medication is 
incomplete or missing, it will be assumed to have occurred on or after the intake of study 
medication, except if an incomplete date (e.g., month and year) clearly indicates that the event 
started prior to treatment. 
13.3.3. 
Populations to be Analyzed 
The populations to be analyzed are as follows: 


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Full Analysis Population: Randomized subjects who received eptinezumab/placebo. Subjects 
will be summarized within the treatment group to which they were randomized. This population 
will be used for efficacy analyses. 
Safety Population: Includes all subjects who received eptinezumab or placebo infusions. Subjects 
will be summarized within the treatment group for which they actually received treatment. This 
population will be used for the safety analyses. 
13.4. 
Statistical Methods 
Continuous variables will be summarized with mean, median, standard deviation, minimum, and 
maximum. Categorical variables will be summarized with frequency and percentage.   
13.4.1. 
Subject Disposition, Demographics and Baseline Characteristics 
An accounting of all randomized study subjects by disposition will be presented. This 
summarization will include a summary of all subjects who have received study drug. 
Demographic, baseline characteristics, migraine history and concomitant medications (coded by 
the World Health Organization Drug Dictionary) will be summarized descriptively by treatment 
group. 
13.4.2. 
Efficacy Analyses 
Primary Efficacy Analyses 
The analysis of the time to pain freedom will be based upon Kaplan-Meier method. The 
treatment difference will be assessed by the stratified log-rank test. A stratified Cox proportional 
hazard model with Efron's method of tie handling will be used to assess the magnitude of the 
treatment difference (i.e., hazard ratio) between the treatment arms. The median estimate for 
each treatment group, hazard ratio and its 95% confidence interval from the stratified Cox model 
with Efron's method of tie handling and with a single treatment covariate will be reported.  The 
analysis of the time to absence of MBS will be conducted similarly. 
Key Secondary Efficacy Analyses 
For each of the 2-hour endpoints, the treatment groups will be compared using a Cochran-
Mantel-Haenszel (CMH) test, adjusting for the study’s stratification factors. The treatment 
difference estimation, odds ratio, and associated confidence intervals will be provided. 
Secondary Efficacy Analyses 
The absence of headache pain (headache pain freedom) at 4 hours, and the absence of most 
bothersome symptom at 4 hours will be analyzed similarly to the key secondary endpoints. 
The use of rescue medication within 24 hours will be analyzed similarly to the key secondary 
endpoints. In case of a missing assessment, it will be assumed that no rescue medication was 
taken in connection with that assessment. 
Exploratory Efficacy Analyses 
Additional exploratory efficacy endpoints will be assessed. 


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13.4.3. 
Safety Analyses 
13.4.3.1. Adverse Events 
The incidence of all AEs will be tabulated by treatment received. These AEs will be classified by 
system organ class and preferred term using the Medical Dictionary for Regulatory Activities 
(MedDRA). For incidence reporting, if a subject reported more than one AE that was coded to 
the same preferred term/system organ class, the subject will be counted only once for that 
specific preferred term/system organ class. Events recorded between the time the informed 
consent is signed and the study drug administration will be provided as part of a listing. 
An overview of AEs, which includes subject incidence of AEs, SAEs, deaths will be presented. 
For AEs presented by severity, the worst severity during the clinical study will be presented for 
each subject. 
The subject incidence of AEs will be summarized by system organ class and preferred term. 
13.4.3.2. Serious Adverse Events 
All SAEs will be listed and summarized in a similar manner to AEs.  
13.4.3.3. Clinical Laboratory Results 
Summary statistics for actual values and for changes from baseline will be tabulated for clinical 
laboratory results by scheduled visit. Subjects with clinical laboratory values outside of the 
normal reference range at any post-baseline assessment will be summarized. Shifts from baseline 
clinical laboratory values based upon the normal range and will be tabulated.  
13.4.3.4. Electrocardiogram (ECG) Results 
The observed data at baseline and change from baseline for each measurement day will be 
summarized with descriptive statistics.   
13.4.3.5. Vital Signs 
The observed data at baseline and change from baseline for each measurement day will be 
summarized with descriptive statistics.  
13.4.3.6. C-SSRS 
The C-SSRS assesses lifetime suicidality during an initial baseline evaluation, and then monitors 
suicidal ideation and suicidal behavior at subsequent follow-up assessments.  Four constructs are 
measured.  The first and second are the severity and intensity of ideation, rated on a 5-point 
ordinal scale.  The third is the behavior subscale, which is rated on a nominal scale and the fourth 
is the lethality subscale, which assesses actual attempts.  These results will be reported at 
baseline and post baseline.  Results for individual time points will be provided in a listing. 


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14. 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
14.1. 
Data Quality Assurance 
The sponsor or designee will assess the site to verify the qualifications of each Investigator, 
according to sponsor’s or applicable SOPs. There will be an inspection of site facilities, and 
investigator will be further informed of responsibilities and the procedures for ensuring adequate 
and correct documentation. 
The investigator is required to prepare and maintain adequate and accurate case histories 
designed to record all observations and other data pertinent to the clinical study for each clinical 
study subject. All information recorded on the CRFs for this clinical study must be consistent 
with the subjects’ source documentation (i.e., medical records). 
14.2. 
Case Report Forms and Source Documents  
As part of the responsibilities assumed by participating in the study, the principal investigator or 
sub-investigator agrees to maintain adequate case histories for the subjects treated as part of the 
research under this protocol. The principal investigator or sub-investigator agrees to maintain 
accurate CRFs and source documentation as part of the case histories. These source documents 
include, but are not limited to, eDiary archives, laboratory reports and original ECGs.  
14.3. 
Study Documentation 
Source document is defined as any hand written or computer-generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, e.g., clinical laboratory reports, clinic notes, drug disbursement log, subject sign 
in sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 
preliminary and pre-final iterations of a final report are also considered to be source documents, 
e.g., faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard 
copy, final report. 
14.4. 
Data Collection and Electronic Data Capture (EDC)  
The data collected during the study (except clinical laboratory test results, ECG results) will be 
recorded in the subject’s CRF. The study site(s) will use an EDC system that is compliant with 
relevant FDA regulatory requirements per 21 CFR Part 11. Data queries and data corrections will 
be handled through the same system. All transactions within the EDC system are fully 
documented within an electronic audit trail. Each set of completed CRFs must be reviewed after 
being source verified by monitor and electronically signed and dated by the investigator. The 
mTOQ-6, HIT-6, PGIC and C-SSRS questionnaires will be completed on paper. The eDiary 
assessments will be collected on the electronic diary (eDiary). 
14.5. 
Archiving Clinical Trial Records 
According to ICH guidelines, essential documents should be retained for a minimum of 2 years 
after the last approval of a marketing application in an ICH region and until there are no pending 
or contemplated marketing applications in an ICH region or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the Investigational Product. However, 


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these documents should be retained for a longer period if required by applicable legal 
requirements.  
It is the responsibility of the investigator and site staff to maintain a comprehensive and 
centralized filing system of all clinical trial-related documentation. This centralized file should 
be available for inspection at any time by the Monitor or Quality Assurance staff for monitoring 
or auditing by Lundbeck Seattle BioPharmaceuticals, Inc. and regulatory authorities. Elements of 
clinical trial documentation should include: 
• Subject files containing the completed CRFs supporting source documentation and 
the signed ICF 
• Clinical trial files, containing the protocol with all amendments, the investigator 
Brochure, copies of all clinical trial documentation, and all correspondence to and 
from the ethics committee and Lundbeck Seattle BioPharmaceuticals, Inc. 
• Pharmacy files, containing the Investigational Product Accountability Records or 
dispensation logs and all clinical trial agent-related correspondence 
14.6. 
Good Clinical Practice 
The procedures set out in this clinical trial protocol are designed to ensure that the sponsor and 
investigator abide by the principles of the GCP guidelines of the ICH and applicable federal and 
local regulations. The clinical trial also will be conducted in keeping with local legal 
requirements. 
14.7. 
Informed Consent 
Before each subject is admitted to the clinical trial, informed consent will be obtained from the 
subject (or his/her legally authorized representative) at the screening visit according to the 
regulatory and legal requirements of the participating country. The consent forms must be dated 
and retained by the investigator as part of the clinical trial records. The Investigator will not 
undertake any investigation specifically required for the clinical trial until valid consent has been 
obtained. The terms of the consent and when it was obtained must also be documented in the 
CRF. Each subject will receive a fully-signed copy of each consent form that he/she signs for the 
clinical trial. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the consent form is revised, it must be reviewed and approved by the appropriate 
ethics committee and signed by all subjects subsequently enrolled in the clinical trial as well as 
those currently enrolled in the clinical trial. If a subject’s partner becomes pregnant during the 
subject’s participation in the trial, a separate pregnancy informed consent form for the pregnant 
partner will be obtained, to allow the sponsor to follow the pregnancy, any complications, and 
the health of the baby.  The pregnancy consent should be obtained at the time the investigator 
becomes aware of the pregnancy. 


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14.8. 
Protocol Approval and Amendment 
Before the start of the clinical trial, the clinical trial protocol and/or other relevant documents 
will be approved by the ethics committee, in accordance with local legal requirements. The 
sponsor must ensure that all ethical and legal requirements have been met before the first subject 
is enrolled in the clinical study. 
The procedures outlined in the protocol and CRFs will be carefully reviewed by the investigator 
and staff prior to clinical study initiation to ensure appropriate interpretation and implementation. 
No deviations from the protocol should be made except in emergency situations where 
alternative treatment is necessary for the protection, proper care and well-being of subjects. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, and 
approvals must be received from the appropriate personnel and from the ethics committee before 
implementation (if appropriate). Amendments will originate from Lundbeck Seattle 
BioPharmaceuticals, Inc., and will be provided to the investigator for submission to his/her ethics 
committee for their review and approval prior to implementation (if appropriate). It should be 
noted that when an amendment to a protocol substantially alters the clinical study design or 
increases potential risk to the clinical study subject, the ICF should be revised and subject’s 
consent to continue participation should be obtained. 
Administrative changes may be made without the need for a formal amendment. All amendments 
will be distributed to all protocol recipients, with appropriate instructions. 
14.8.1. 
Premature Termination of the Clinical Study 
Lundbeck Seattle BioPharmaceuticals, Inc., reserves the right to terminate this clinical study at 
any time. The FDA or other governing national authority may also terminate the clinical study. 
The principal investigator may discontinue participation in the study. If the clinical study is 
terminated prior to scheduled completion, the investigator will be notified and given any 
necessary instructions concerning final examinations that are required. If the investigator, the 
sponsor, or the medical monitor becomes aware of conditions or events that suggest a possible 
safety hazard to subjects if the clinical study continues, the clinical study may be terminated after 
appropriate consultation between the relevant parties.  
14.9. 
Confidentiality 
All clinical study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the sponsor. 
The anonymity of participating subjects must be maintained. Subjects will be identified on CRFs 
and other documents by their subject number, initials and/or birth date, not by name and in 
accordance with local requirements. Documents not to be submitted that identify the subject 
(e.g., the signed informed consent) must be maintained in confidence by the investigator.  


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14.10. 
Publication Policy 
By signing the clinical study protocol, the Investigator agrees with the use of results of the 
clinical study for the purposes of national and international registration, publication, and 
information for medical and pharmaceutical professionals. If necessary, the authorities will be 
notified of the investigator's name, address, qualifications, and extent of involvement. 
An investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted 
and received written permission by the sponsor in advance. The information provided in support 
of or generated as a result of this clinical study is confidential. Any use or reproduction thereof, 
including but not limited to publications or presentations by the investigator or his/her associates, 
must be submitted to Lundbeck Seattle BioPharmaceuticals, Inc., for review and approval in 
accordance with the provisions contained in the clinical study agreement. All publications must 
acknowledge the sponsorship of Lundbeck Seattle BioPharmaceuticals, Inc. 
All information not previously published concerning eptinezumab and Lundbeck Seattle 
BioPharmaceuticals, Inc., operations, including but not limited to patent applications, formulas, 
manufacturing processes, basic scientific data, and formulation information, supplied by 
Lundbeck Seattle BioPharmaceuticals, Inc., to the investigator is considered confidential and 
shall remain the sole property of Lundbeck Seattle BioPharmaceuticals, Inc. The investigator 
agrees to use and maintain the confidentiality of this information in accordance with the 
provisions contained in the clinical study agreement. 
 


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15. 
APPENDICES 
15.1. 
Migraine preventive therapies with established or probable efficacy 
(Esternalik, 2013), (Antonaci, 2010), (Pringsheim, 2012) 
• 
Angiotensin converting enzyme inhibitor (ACE inhibitor) 
− 
Lisinopril 
− 
Candesartan 
• 
anti-CGRP monoclonal antibody 
− 
Erenumab 
− 
Fremanezumab 
− 
Galacanezumab 
• 
Anti-epileptic drug (AED) 
− 
Divalproex sodium 
− 
Valproic Acid 
− 
Topiramate 
− 
Gabapentin 
− 
Lamotrigene 
• 
Beta blocker 
− 
Metoprolol 
− 
Propranolol 
− 
Timolol 
− 
Atenolol 
− 
Nadolol 
− 
Bisoprolol 
• 
Calcium channel blocker 
− 
Verapamil 
• 
Herbal 
− 
Butterbur 
− 
Feverfew 
• 
Selective serotonin norepinephrine reuptake inhibitor (SNRI) 
− 
Venlafaxine 
• 
Selective serotonin reuptake inhibitor (SSRI) 
− 
Fluoxetine 


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• 
Tricyclic (TCA) 
− 
Amitriptyline 
• 
Triptan 
− 
Frovatriptan* 
− 
Naratriptan* 
− 
Zolmitriptan* 
Other drugs for prophylaxis will be considered on a case by case basis. 
*only considered prophylaxis when specifically used as such (e.g., menstrually-related migraine (MRM)) 


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15.2. 
Columbia-Suicide Severity Rating Scale (C-SSRS) Risk Assessment  
15.2.1. 
Baseline/Screening Version 


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15.2.2. 
Since Last Visit Version 
 


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15.3. 
Migraine Treatment Optimization Questionnaire- 6 (MTOQ-6) 
 
 
 
 
 
 
 
 
 
 


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15.4. 
Patient Global Impression of Change (PGIC) 
 


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15.5. 
Headache Impact Test (HIT-6 v1.0) 
 
 


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16. 
REFERENCES 
Antonaci F, Dumitrache C, De Cillis I, Allena M.  A review of current European treatment 
guidelines for migraine.  J Headache Pain.  2010; 11: 13-19. 
Cady RJ, Shade CL, Cady RK. Advances in drug development for acute migraine. Drugs. 
2012:72(17):1-19. 
Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache. 2006; 46(Suppl 
1):S3-S8. 
Durham PL. CGRP-receptor antagonists—a fresh approach to migraine therapy? N Engl J Med. 
2004; 350:1073-1075. 
Esternalik E, Tepper S.  Preventive treatment in migraine and the new US guidelines.  
Neuropsychiatr Dis Treat. 2013; 9; 709-720.  
Hansen JM, Hauge AW, Olesen J, Ashina M. Calcitonin gene-related peptide triggers migraine-
like attacks in patients with migraine with aura. Cephalalgia. 2010; 30(10):1179-1186. 
Headache Classification Committee of the International Headache Society. The International 
Classification of Headache Disorders, 3rd edition. Cephalalgia. 2018, 38(1) 1–211. 
Katsarava, Buse D. Defining differences between episodic and chronic migraine. Curr Pain and 
Headache. 2012; 1:86-92. 
Leonardi M, Steiner TJ, Scher AT, Lipton RB. The global burden of migraine: measuring 
disability in headache disorders with WHO’s classification of functioning, disability and health 
(ICF). J Headache Pain. 2005; 6(6):429-440. 
Lipton R, Bigal M, Diamond M, Freitag F, Reed M, Stewart W. Migraine prevalence, disease 
burden, and the need for preventive therapy. Neurology. 2007; 68:343-349. 
MacGregor, E. Anne & Brandes, Jan & Silberstein, Stephen & Jeka, Sławomir & Czapinski, 
Piotr & Shaw, Bob & Pawsey, Stephen. (2009). Safety and Tolerability of Short-Term 
Preventive Frovatriptan: A Combined Analysis. Headache. 49. 1298-314. 10.1111/j.1526-
4610.2009.01513.x. 
Pringsheim T, Davenport W, Mackie G, et al. Canadian Headache Society Guideline for 
Migraine Prophylaxis - Section II.  Can J Neurol Sci 2012; 39: Suppl. 2 – S8-28. 
Schmid CW, Konrad M, Schmid DM, et al. the Journal of Headache and Pain 2013; 14:4 
Stewart WF, Ricci JA, Chee E, et al. Lost productive work time costs from health conditions in 
the United States: results from the American Productivity Audit J Occup Environ Med 2003; 
45(12): 1234-1246. 
United States Food and Drug Administration, United States Department of Health and Human 
Services. Guidance for Industry: Suicidal Ideation and Behavior: Prospective Assessment of 
Occurrence in Clinical Trials, Draft Guidance. August 2012. Revision 1.  

SAP_001.pdf: 
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H. Lundbeck A/S
Statistical Analysis Plan
Protocol Numbers
18903A
Investigational Product
Eptinezumab (Lu AG09221)
Sponsor
H. Lundbeck A/S
Ottiliavej 9
2500 Valby
Denmark
Date of SAP (Version 3.0)
04AUG 2020
Confidential Information
The information contained in this document is confidential and may not be reproduced or the 
contents disclosed, in whole or in part, without written authorization of H. Lundbeck A/S. 
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Table of Contents
List of Tables...................................................................................................................5
LIST OF ABBREVIATIONS.............................................................................................6
1.
INTRODUCTION......................................................................................................8
2.
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS ....................................8
2.1.
Protocol and Case Report Form Version...........................................................8
2.2.
Study Objectives ...............................................................................................8
2.2.1.
Primary Objective.......................................................................................8
2.2.2.
Secondary Objectives ................................................................................8
2.3.
Study Endpoints................................................................................................9
2.3.1.
Co-Primary Endpoints................................................................................9
2.3.2.
Key Secondary Endpoints..........................................................................9
2.3.3.
Secondary Endpoints.................................................................................9
2.3.4.
Exploratory Endpoints................................................................................9
2.3.5.
Safety Endpoints......................................................................................10
3.
STUDY DESIGN....................................................................................................10
3.1.
Study Design Description................................................................................10
3.2.
Randomization................................................................................................10
3.3.
Sample Size Considerations ...........................................................................11
3.4.
Multiplicity .......................................................................................................11
4.
STATISTICAL METHODOLOGY ...........................................................................12
4.1.
General Methodology......................................................................................12
4.2.
Analysis Populations.......................................................................................13
4.3.
Statistical Methods for Efficacy Analyses ........................................................13
4.3.1.
Co-Primary Efficacy Endpoints.................................................................13
4.3.2.
Key Secondary Efficacy Endpoints...........................................................16
4.3.3.
Secondary Efficacy Endpoints..................................................................18
4.3.4.
Exploratory Efficacy Analyses..................................................................19
4.3.5.
Sensitivity Analyses .................................................................................23
4.3.6.
Subgroup Analyses for Primary Endpoint.................................................24
5.
BASELINE, DISPOSITION, AND EXPOSURE.......................................................25
5.1.
Study Day Analysis Window............................................................................25
5.2.
Definition of Baseline ......................................................................................25
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5.3.
Demographics and Baseline Characteristics ...................................................25
5.3.1.
Qualifying Migraine Assessment and baseline score................................26
5.4.
Subject Disposition..........................................................................................26
5.5.
Prior and Concomitant Medications.................................................................26
5.6.
Medical History................................................................................................27
5.7.
Migraine History ..............................................................................................27
5.8.
Study Drug Exposure......................................................................................28
5.9.
eDiary Compliance..........................................................................................28
6.
ANALYSIS OF SAFETY ENDPOINTS ...................................................................28
6.1.
Adverse Events...............................................................................................28
6.1.1.
Adverse events of special interest............................................................30
6.2.
Clinical Laboratory Evaluations .......................................................................32
6.2.1.
Potential Drug-induced Liver Injury (DILI).................................................34
6.3.
Vital Signs.......................................................................................................34
6.4.
Electrocardiogram Results ..............................................................................35
6.5.
Columbia-Suicide Severity Rating Scale (C-SSRS).........................................36
6.6.
Pregnancies....................................................................................................36
6.7.
Other...............................................................................................................36
7.
Changes to Analyses Specified in the Protocol ......................................................37
8.
Appendix I..............................................................................................................38
9.
Appendix II.............................................................................................................42
9.1.
SAS® Code......................................................................................................42
9.1.1.
Cox proportional hazards model...............................................................42
9.1.2.
Cochran-Mantel-Haenszel test.................................................................43
10.
Appendix III ........................................................................................................44
11.
References.........................................................................................................48
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LIST OF TABLES
Table 1
Analysis Windows ................................................................................................25
Table 2
Schedule of Events and Assessments ...................................................................38
Table 3
Schedule of Events and Assessments for Day 0 through 48 Hours.....................40
Table 4
PCS Criteria for Clinical Safety Laboratory Tests.............................................44
Table 5
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference..............46
Table 6
PCS Criteria for ECG Parameters......................................................................47
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LIST OF ABBREVIATIONS
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase  
ANCOVA
Analysis of Covariance
AST
Aspartate aminotransferase
BMI
Body Mass Index
CMH
Cochran-Mantel-Haenszel 
CRF
Case Report Form
C-SSRS
Columbia-Suicide Severity Rating Scale
ECG
Electrocardiogram
eDiary
Electronic Diary
HIT-6
Headache Impact Test
kg
Kilogram
kg/m2
Kilogram per Meter Squared
MBS
Most Bothersome Symptom
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MOH
Medication Overuse Headache
MTOQ-6
Migraine Treatment Optimization Questionnaire-6
NSAID
Non-steroidal anti-inflammatory drug
PCS
Potentially clinically significant
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PGIC
Patient Global Impression of Change
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SD
Standard Deviation
SE
Standard Error
SOC
System Organ Class
TEAE
Treatment-emergent Adverse Event
TLF
Table, Listing and Figure
ULN
Upper Limit of Normal
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1.
INTRODUCTION
This is a parallel group, double-blind, randomized, placebo-controlled study assessing the 
efficacy of eptinezumab for acute migraine, as defined as an active intercurrent migraine 
occurring in those patients who are candidates for preventive therapy. The patients
randomized to the eptinezumab treatment group will receive an IV infusion of 
eptinezumab and the patients randomized to placebo will receive an IV infusion of 
placebo. See study protocol Section 9 for more details on the study drug. 
Section 5 of the Protocol provides a detailed description of the investigational product, 
target patient population, rationale for doses to be examined, and potential risks and 
benefits of treatment with eptinezumab. The purpose of this Statistical Analysis Plan 
(SAP) is to define the methodology for analyzing and summarizing the data collected 
during the conduct of Study 18903A, previously ALD403-CLIN-015. The study will be 
referenced as 18903A throughout this document.
2.
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS
2.1.
Protocol and Case Report Form Version
This SAP is based on 18903A (previously ALD403-CLIN-015) Protocol including 
Amendment 2 dated 06DEC2019 and case report forms (CRFs) approved 15OCT2019.  
Unless superseded by an amendment, this SAP will be effective for all subsequent 
Protocol amendments and CRF versions.
2.2.
Study Objectives 
2.2.1.
Primary Objective
The primary objective of the study is: To evaluate the effect of eptinezumab compared to 
placebo with respect to time to headache pain freedom AND time to absence of most 
bothersome symptom during an intercurrent migraine that occurs in subjects who are 
candidates for preventive therapy.
2.2.2.
Secondary Objectives
The secondary objectives of the study are to evaluate the efficacy of eptinezumab vs. 
placebo on:

Headache pain freedom at timepoints up to 48 hours

Absence of most bothersome symptom at timepoints up to 48 hours

Time to headache pain relief

Sustained headache pain freedom from 2 – 48 hours
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
Acute rescue medication use 

Effect on symptoms of the qualifying migraine

Effect on patient-reported outcomes
2.3.
Study Endpoints
2.3.1.
Co-Primary Endpoints

Time to headache pain freedom 

Time to absence of most bothersome symptom
2.3.2.
Key Secondary Endpoints

Headache pain freedom at 2 hours

Absence of most bothersome symptom at 2 hours
2.3.3.
Secondary Endpoints

Absence of headache pain at 4 hours

Absence of most bothersome symptom at 4 hours

Use of rescue medication within the first 24 hours
2.3.4.
Exploratory Endpoints

Time to headache pain relief

Heachache pain relief at 2 hours

Heachache pain relief at 4 hours

Headache pain freedom at 2 hours with sustained headache pain freedom for 
24 and 48 hours

Use of rescue medication within the first 48 hours

Absence of photophobia at all timepoints

Absence of phonophobia at all timepoints

Absence of nausea at all timepoints

Change from Baseline in Headache Impact Test (HIT-6) at Week 4

Change from Baseline in Migraine Treatment Optimization Questionnaire-6 
(mTOQ-6) at Week 4

Absence of headache pain at all timepoints other than 2 and 4 hours
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
Patient Global Impression of Change (PGIC) at Week 4

Time to next migraine

Time to first rescue medication
2.3.5.
Safety Endpoints

Adverse events (AEs) and serious adverse events (SAEs)

Clinical laboratory assessments

Vital signs

Electrocardiograms (ECGs)

Columbia-Suicide Severity Rating Scale (C-SSRS)
3.
STUDY DESIGN
3.1.
Study Design Description
The total study duration will be approximately 4 to 12 weeks, including up to 8-week 
screening period, with clinic visits occurring on Screening, Day 0 (dosing day), and 
Week 4. See Table 2 and Table 3 for schedules of events and assessments for the whole 
study and for Day 0 through 48 hours. 
Randomization and dosing will be triggered by a qualifying migraine and will occur on 
Day 0. Study design requires that study drug administration be initiated within 1 to 6 
hours of migraine onset, and subjects must be willing and able to travel to the site for 
study drug administration within this time frame. Subjects must remain at the site for 4-
hours post start-of-infusion for observation. Subjects may be followed longer than 4 
weeks, if necessary, for safety follow-up as described in the protocol. An eDiary will be 
assigned prior to dosing at the Day 0 visit and dosed subjects must complete the eDiary at 
prescribed timepoints (just before infusion, and after 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 
24, and 48 hours post start of infusion) through 48 hours after start of infusion (t=0). 
Additionally, subjects will complete daily eDiary data entry from Day 3 until a new 
migraine is reported.
3.2.
Randomization
Subjects will be randomized to receive either 100 mg eptinezumab or placebo in a 1:1 
ratio. Randomization will be stratified by concomitant migraine preventative treatment 
(concomitant migraine preventative treatment use vs. no concomitant migraine 
preventative treatment use) and region (North America vs. Rest of World).
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3.3.
Sample Size Considerations
The planned sample size for this study is 450 randomized and dosed subjects. These 
subjects will be allocated into 2 treatment groups, eptinezumab vs. placebo, in a 1:1 ratio. 
Two hundred twenty-five subjects per group provides at least 90% power to detect a 
0.736 hazard ratio favouring eptinezumab at the 5% significance level for both co-
primary endpoints. Based on simulations, it has been shown that this sample size also 
provides 90% power for the key secondary endpoints, assuming a rate of 20% for the 
placebo group and a rate of 34.5% for the eptinezumab group, i.e. that eptinezumab 
increases response rates for both 2-hour endpoints by at least 14.5 percentage points at a 
5% significance level, where the correlation between the two endpoints is assumed to be 
0.8.
3.4.
Multiplicity
To show effect on the co-primary endpoints, it is required to achieve statistical 
significance on a 5% significance level simultaneously for both of the primary endpoints, 
and therefore no multiplicity adjustment is done for the primary endpoints. If both co-
primary endpoints achieve statistical significance at a 5% significance level, the key 
secondary endpoints will be tested hierarchically at a 5% significance level. First the pain 
freedom at 2 hours will be tested at a 5% significance level and if a statistically 
significant effect is seen, testing will continue with the absence from most bothersome 
symptom at 2 hours at a 5% significance level. If both key secondary endpoints achieve 
statistical significance, the secondary endpoints will be tested hierarchically at an overall 
5% level of significance. First absence of headache pain at 4 hours will be tested at 5% 
level of significance, and if statistically significant, the absence of the most bothersome 
symptom at 4 hours will be at 5% level of significance. If also the second test is 
statistically significant, the use of rescue medication within the first 24 hours will be 
tested at 5% level of significance. All tests will be 2-sided.
All other endpoints will use a 2-sided 5% significance level with no adjustment for 
multiplicity. If the hierarchical testing strategy is stopped at any stage due to insignificant 
results, the remaining key secondary and/or secondary endpoints will not be part of the 
formal testing, but nominal p-values will be presented.
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4.
STATISTICAL METHODOLOGY
4.1.
General Methodology
Unless otherwise stated, SASsoftware Version 9.4 or later will be used for the 
generation of all tables, graphs, and statistical analyses. SAScode for performing the 
analyses of the co-primary and key secondary endpoints can be found in Appendix II. 
For all efficacy endpoints, summary tables with descriptive statistics will be included 
taking into account the type of endpoint as outlined below. For some endpoints, the 
summary tables are further described in the sections related to the specific endpoint.
Summary statistics including the number of subjects (n), mean, standard deviation, 
median, minimum and maximum will be presented for continuous variables. Generally, 
the minimum and maximum values will be presented to the same decimal precision as the 
raw values, the mean and median values to one more, and the standard deviation, to two 
more decimal places than the raw values. For categorical variables, per category, the 
absolute counts (n) and percentages (%) of subjects with data, and if appropriate, the 
number of subjects with missing data, will be presented. Percentages will be presented to 
one decimal place.
For time-to-event endpoints, the descriptive statistics that will be presented are the 
number of patients included in the analysis, the number of patients that experienced an 
event, and a table displaying for each timepoint where events occurred, how many 
patients were at risk and how many patients experienced an event at the timepoint. 
For binary endpoints, crosstables will be presented displaying the number and percentage 
of patients in each treatment group that fulfill the definition related to the specific 
endpoint.
Summary statistics will be reported based upon observed data. For statistical analysis
purposes, rules for handling missing data will be applied and these are described in the 
following sections.
For AEs, medical history and concomitant medications reported on a per-subject basis, 
the denominator for the percentage calculation will be the number of subjects at risk in 
each treatment group. A subject will be considered at risk if the subject is in the analysis 
set and in the subgroup of interest.
All nominal p-values will be based on 2-sided tests. See Section 3.4 for description of the 
significance levels used.
If a p-value is less than 0.0001 it will be displayed as “< 0.0001”. All p-values larger than 
0.0001 will be rounded to 4 decimal places.
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4.2.
Analysis Populations
The analysis populations are defined as the following:

Full Analysis Population (FAP) – Includes all randomized subjects who received
eptinezumab or placebo. Subjects will be summarized within the treatment group 
to which they were randomized. This population will be used for all efficacy 
analyses.

Safety Population – Includes all subjects who received eptinezumab or placebo. 
Subjects will be summarized within the treatment group for which they actually 
received treatment. This population will be used for the safety analyses.
4.3.
Statistical Methods for Efficacy Analyses
4.3.1.
Co-Primary Efficacy Endpoints
Hypothesis testing will be performed for the co-primary endpoints:
-
Time to headache pain freedom
-
Time to absence of most bothersome symptom (MBS)
4.3.1.1.
Primary Estimands
In line with the recently released addendum to the ICH E9 guideline on estimands and 
sensitivity analysis in clinical trials1, descriptions of the primary and key secondary 
estimands are included in this document.  
To further clarify the estimands, estimand attributes (treatment condition of interest, the 
population of interest, the variable that will be used to address the clinical question, and 
the population-level summary for the variable) will be included. Furthermore, a 
description of the potential intercurrent events that may affect the clinical question of 
interest and the strategy used to handle the intercurrent events will be included.  
4.3.1.1.1. Intercurrent Events
Potential intercurrent events occurring after treatment initiation that affect the 
interpretation of the primary endpoints include use of rescue medication, sleep, and 
death.
Given the duration of the study and the population included, no deaths are expected. 
Therefore, handling of death as an intercurrent event will not be pre-specified.
Sleep may have a beneficial effect on migraine. During the 48 hours of data collection of 
the primary endpoints, sleep will only be collected indirectly via the collection of whether 
the patient was asleep or awake at the timepoints where pain and MBS symptom status 
are collected. This is insufficient to address the impact of sleep as an intercurrent event 
on the ongoing migraine. 
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In this study, rescue medication is defined as

Medication use collected through the eDiary that is taken after start of 
infusion
It is expected that the majority of the rescue medications used in the study will belong to 
one of the following 3 categories: Triptans, NSAIDs, and analgesics. These are all 
characterized by potentially working fast and having an immediate effect on pain as well 
as all 3 types of MBS. This implies that the status of the patient after use of rescue 
medication could be a consequence of the rescue medication rather than a result of the 
randomized treatment. Since the effect of interest is the pharmacological effect of 
eptinezumab, this intercurrent event will be addressed using a hypothetical strategy by 
disregarding information obtained after the use of rescue medication. The hypothetical 
scenario that is envisaged is one where rescue medication is not available.
4.3.1.1.2. Estimands
The clinical question of interest is whether pain freedom and absence of MBS can be 
achieved faster with eptinezumab than with placebo. 
The primary estimands defined to answer this question are the following:

The hypothetical effect of eptinezumab on time to pain freedom that would be 
seen in a population where no rescue medication was available

The hypothetical effect of eptinezumab on time to absence of MBS that would 
be seen in a population where no rescue medication was available
The estimand attributes are as follows:
Treatment condition of interest
The treatment condition of interest is eptinezumab 100 mg compared to placebo for both 
primary estimands. 
Population
The population for both primary estimands is the entire study population that is, subjects 
who are candidates for preventive therapy defined by fulfilling the inclusion and 
exclusion criteria.  
Variables
Headache pain will be collected on a 4-point scale with 3 being severe, 2 being moderate, 
1 being mild, and 0 being no pain.
MBS is the symptom from among nausea, photophobia (light sensitivity), or 
phonophobia (sound sensitivity) that has been identified by the patient on Day 1 prior to 
dosing as being the most bothersome one for the migraine being treated. 
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The patient is asked to report headache pain and whether each of the 3 symptoms are 
present at specified time points after the infusion.
For the primary estimands, the variables that address the clinical question of interest are 
the following:

Time to pain freedom. The time is calculated from the start of infusion to the 
first time point post infusion with a rating of no pain, within the first 48 hours 
after infusion start

Time to absence of MBS. Time is calculated from the start of infusion to the 
first time point post infusion where absence of MBS is recorded, within the 
first 48 hours after infusion start
Intercurrent Events
The intercurrent event of taking rescue medication prior to obtaining pain 
freedom/absence of MBS will be addressed using a hypothetical strategy by disregarding
information obtained after the use of rescue medication. No other intercurrent events will 
be addressed. 
Population level summary
The population level summary for both variables defined above will be the hazard ratio 
(HR) between eptinezumab and placebo.
4.3.1.1.3. Primary Analysis
The two co-primary endpoints will be analyzed similarly but separately and the analyses 
will be based on the FAP.
The endpoints are collected at the following pre-specified timepoints: Just before 
infusion, and after 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, and 48 hours post start of 
infusion, see also Table 3. 
For conducting the analyses, the following derivations will apply to each of the 
endpoints:

If a patient reports pain freedom/absence of MBS without having reported use 
of rescue medication up to and including the timepoint where pain 
freedom/absence of MBS is reported, the first collected timepont of pain 
freedom/absence of MBS will be used for analysis (status indicator equals 1,
indicating pain freedom obtained)

If a patient reports taking rescue medication without having reported pain 
freedom/absence of MBS at an earlier timepoint, the timepoint of first rescue 
medication reporting is the value that will be used in the analysis (status 
indicator equals 0, indicating censoring at the time of rescue medication)
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
If a patient does not report pain freedom/absence of MBS during the 48 hours
and does not report taking rescue medication at any timepoint, the timepoint 
of the last entry in the eDiary for the 48 hours will be used in the analysis 
(status indicator equals 0, indicating administrative censoring)
Summary tables as described in section 4.1 will be provided for each treatment group for 
both co-primary endpoints.
The HR for time to headache pain freedom/time to absence of MBS between 
eptinezumab and placebo, will be estimated from a stratified Cox proportional hazards 
model with a single treatment covariate and using Efron’s method of tie handling. The 
stratification factors will be identical to the factors used for randomization. 
The HR will be reported together with its 95% confidence interval. The confidence 
interval will be computed from the profile likelihood. The median estimate for time to 
pain freedom/absence of MBS for each treatment group from the stratified Cox model 
will also be reported. For computing median estimates of time to pain freedom/time to 
absence of MBS for each treatment group, the estimated survival curves from the Cox 
model for each stratum will be combined using a weighted average of the curves for each 
stratum. The weights will equal the number of patients in the stratum divided by the total 
number of patients included in the analysis. Plots of the combined survival curves across 
strata from the stratified Cox model will be presented by treatment group, as well as plots 
of the estimated survival curves from the stratified Cox model by stratum and treatment 
group.
The likelihood ratio test from this model, testing whether the hazard ratio between the 
two treatments equals 1 (whether the parameter for the treatment effect is equal to 0) will 
be used for testing whether there is an advantage of the eptinezumab treatment over 
placebo. 
Kaplan-Meier plots for time to pain freedom and time to absence of MBS will be 
presented for each treatment group.
SAS® code for the primary analyses is given in Appendix II.
4.3.2.
Key Secondary Efficacy Endpoints
Hypothesis testing will be performed for the key secondary endpoints: 
-
Headache pain freedom at 2 hours
-
Absence of most bothersome symptom at 2 hours
4.3.2.1.
Key Secondary Estimands
Like for the co-primary endpoints, estimands related to the key secondary endpoints will 
be described.
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4.3.2.1.1. Intercurrent Events
For the key secondary endpoints, the potential intercurrent event: use of rescue 
medication is expected to happen only in a limited number of instances prior to observing 
the key secondary endpoints after 2 hours, as the protocol requests that no rescue 
medication is taken prior to 2 hours. But as the occurrence might have a substantial 
impact on the endpoints, it will still be considered.
Since the use of rescue medication prior to the 2-hour assessments could result in 
considerable improvement that would not be due to the randomized treatments, a 
composite strategy will be used to address this intercurrent event for the key secondary 
endpoints. Thus, to obtain the result of either pain freedom or absence of MBS at 2 hours, 
it is required to do so without prior use of rescue medication. 
4.3.2.1.2. Estimands
The clinical question of interest is whether more patients experience pain freedoom and 
absence of MBS after two hours post infusion with eptinezumab than with placebo.
The key secondary estimands defined to answer this question are the following:

The effect of eptinezumab on number of patients obtaining pain freedom at 2 
hours post start of infusion without the use of rescue medication

The effect of eptinezumab on number of patients obtaining absence of MBS at
2 hours post start of infusion without the use of rescue medication
The estimands’ attributes are as follows:
Treatment condition of interest
The treatment condition of interest is eptinezumab 100 mg compared to placebo for both 
key secondary estimands. 
Population
The population for both key secondary estimands is the entire study population that is, 
subjects who are candidates for preventive therapy defined by fulfilling the inclusion and 
exclusion criteria.  
Variables
For the key secondary estimands, the variables that address the clinical question of 
interest are the following:

Binary response variable indicating a successful response if a patient achieves 
headache pain freedom at 2 hours post start of infusion without any prior 
administration of rescue medication
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
Binary response variable indicating a successful response if a patient achieves 
absence of MBS at 2 hours post start of infusion without any prior 
administration of rescue medication
Intercurrent events
As the intercurrent event of use of rescue medication has been addressed directly in the 
definition of the composite endpoint, there are no other intercurrent events to address.
Population level summary
The population level summary for both variables defined above will be the difference in 
response proportions between treatment conditions (eptinezumab and placebo).
4.3.2.1.3. Key Secondary Analysis
The two key secondary endpoints will be analyzed similarly but separately, and the 
analyses will be based on the FAP.
Obtaining headache pain freedom at 2 hours is defined as having a measurement at 2 
hours, and not having pain at 2 hours, and not taking rescue medication prior to or at the 
2 hours assessment. All other patients are considered to not have obtained pain freedom 
at 2 hours. The endpoint of obtaining absence of MBS at 2 hours is similarly defined.
For each of the two key secondary endpoints, the treatment groups will be compared 
using a Cochran-Mantel-Haenszel (CMH) test, adjusting for the study’s stratification 
factors; concomitant migraine preventive treatment use and region.
The Mantel-Haenszel estimate of the common odds ratio and associated confidence 
intervals will be provided.
Furthermore, the difference in rates and associated confidence interval will be calculated 
based on the normal approximation of two independent proportions without taking the 
stratification factors into account.
SAS® code for the key secondary analyses is given in Appendix II.
Plots of the proportion of patients achieving pain freedom and absence of their MBS 
across time (baseline, 0.5 hours, 1 hour, 1.5 hours and 2 hours), for each treatment group, 
will be produced. If the pain or MBS assessment is missing at a given timepoint, it is 
assumed that no pain freedom or no absence of MBS has been obtained for this 
timepoint.
4.3.3.
Secondary Efficacy Endpoints
The absence of headache pain (headache pain freedom) at 4 hours, and the absence of 
most bothersome symptom at 4 hours will be analysed similarly to the key secondary
endpoints described in section 4.3.2.1.3. The analyses will be based on the FAP unless 
otherwise specified.
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Use of rescue medication by 24 hours is defined as having a measurement of use of 
rescue medication within the first 24 hours. In case of a missing assessment, it will be 
assumed that no rescue medication was taken in connection with that assessment. The 
endpoint will then be analysed similarly to the key secondary endpoints described in 
section 4.3.2.1.3 using the definition above.
4.3.4.
Exploratory Efficacy Analyses
All exploratory efficacy endpoints will be assessed descriptively or tested at a 2-sided 5% 
alpha with no adjustment for multiplicity and be based on the FAP.
Time to headache pain relief
Headache pain relief is defined as a rating of mild or no pain (rating of 1 or 0). Time to 
headache pain relief is defined similarly to the time to headache pain freedom, i.e. time 
from start of infusion to the first timepoint post infusion with pain relief, within the first 
48 hours after infusion start.
Handling of rescue medication and missing timepoints will be done according to the rules 
for the co-primary endpoints defined in section 4.3.1.1.3. 
Time to headache pain relief will be analysed similarly to the two co-primary endpoints 
described in section 4.3.1.1.3. 
Headache pain relief at 2 and 4 hours
Headache pain relief at 2 and 4 hours post-dose will be assessed using 4-point Likert
scale, where patients report a pain level of mild or no pain (rating of 1 or 0) at 2 and 4 
hours post-dose, respectively.
The endpoints will then be analysed similarly to the key secondary endpoints described in 
section 4.3.2.1.3 using the definition above.
Headache pain freedom at 2 hours with sustained headache pain freedom for 24 
hours 
Obtaining headache pain freedom at 2 hours with sustained headache pain freedom for 24 
hours is defined as having an available measurement at 2 hours, 2.5 hours, 3 hours, 3.5 
hours, 4 hours, 6 hours, 9 hours, 12 hours, and 24 hours, and not having pain at 2 hours, 
2.5 hours, 3 hours, 3.5 hours, 4 hours, 6 hours, 9 hours, 12 hours, and 24 hours, and not 
taking rescue medication prior to or at the 24 hours assessment. All other patients are 
considered to not have headache pain freedom at 2 hours with sustained headache pain 
freedom for 24 hours.
The endpoint will then be analysed similarly to the key secondary endpoints described in 
section 4.3.2.1.3 using the definition above.
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Headache pain freedom at 2 hours with sustained headache pain freedom for 48 
hours
Obtaining headache pain freedom at 2 hours with sustained headache pain freedom for 48 
hours is defined as having an available measurement at 2 hours, 2.5 hours, 3 hours, 3.5 
hours, 4 hours, 6 hours, 9 hours, 12 hours, 24 hours, and 48 hours, and not having pain at 
2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 6 hours, 9 hours, 12 hours, 24 hours, and 
48 hours, and not taking rescue medication prior to or at the 48 hours assessment. All 
other patients are considered to not have headache pain freedom at 2 hours with sustained 
headache pain freedom for 48 hours.
The endpoint will then be analysed similarly to the key secondary endpoints described in 
section 4.3.2.1.3 using the definition above.
Use of rescue medication by 48 hours
Use of rescue medication by 48 hours is defined as having a measurement of use of 
rescue medication within the first 48 hours. In case of a missing assessment, it will be 
assumed that no rescue medication was taken in connection with that assessment.
The endpoint will then be analysed similarly to the key secondary endpoints described in 
section 4.3.2.1.3 using the definition above.
Absence of photophobia (light sensitivity) at all timepoints
The subgroup of patients with photophobia (light sensitivity) is defined as the subgroup 
of patients in the FAP who answer ‘Yes’ to the eDiary question “Do you have light 
sensitivity?” at baseline. The absence of photophobia will be presented for each timepoint 
separately.
Absence of photophobia at X hours is defined as having a record of no photophobia at X 
hours and not taking rescue medication prior to or at the X-hour assessment. All other 
patients are considered not to have obtained the endpoint.
The endpoint will then be analysed similarly to the key secondary endpoints described in 
section 4.3.2.1.3, but only for the sub-population of patients with photophobia at baseline.
In addition, cross tables displaying the number and percentage of patients with or without 
photophobia at baseline that do or do not experience photophobia will be presented for 
each treatment group and timepoint based on the full FAP.
Absence of phonophobia (sound sensitivity) at all timepoints
The subgroup of patients with phonophobia (sound sensitivity) is defined as the subgroup 
of patients in the FAP who answer ‘Yes’ to the eDiary question “Do you have sound
sensitivity?” at baseline. The absence of phonophobia will be presented for each 
timepoint separately.
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Absence of phonophobia at X hours is defined as having a record of no phonophobia at X 
hours and not taking rescue medication prior to or at the X-hour assessment. All other 
patients are considered not to have obtained the endpoint.
The endpoint will then be analysed similarly to the key secondary endpoints described in 
section 4.3.2.1.3, but only for the sub-population of patients with phonophobia at 
baseline.
In addition, cross tables displaying the number and percentage of patients with or without 
phonophobia at baseline that do or do not experience phonophobia will be presented for 
each treatment group and timepoint based on the full FAP.
Absence of nausea at all timepoints
The subgroup of patients with nausea is defined as the subgroup of patients in the FAP 
who answer ‘Yes’ to the eDiary question “Do you have nausea?” at baseline. The 
absence of nausea will be presented for each timepoint separately.
Absence of nausea at X hours is defined as having a record of no nausea at X hours and 
not taking rescue medication prior to or at the X-hour assessment. All other patients are 
considered not to have obtained the endpoint. 
The endpoint will then be analysed similarly to the key secondary endpoints described in 
section 4.3.2.1.3 but only for the sub-population of patients with nausea at baseline.
In addition, cross tables displaying the number and percentage of patients with or without 
nausea at baseline that do or do not experience nausea will be presented for each 
treatment group and timepoint based on the full FAP.
Change from Baseline in Headache Impact Test (HIT-6) at Week 4
The Headache Impact Test (HIT) is a tool used to measure the impact and effect on the 
ability to function normal in daily life when a headache occurs. The HIT is a 6 question, 
Likert-type, selfreporting questionnaire with responses ranging from “Never” to 
“Always” with the following response scores: Never=6, Rarely=8, Sometimes=10, Very 
Often=11, Always=13. The total score for the HIT is the sum of each response score and 
will be treated as missing if the response is missing for one or more questions. The HIT 
total score ranges from 36 to 78, with score ranges having the following life impact:
Score Range
Life Impact
>=60
Severe
56-59
Substantial
50-55
Some
<=49
Little to None
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The actual score and change from baseline for the total score will be summarized at each 
scheduled visit by treatment group. A shift from baseline to the week 4 visit by treatment 
group will be tabulated for each item. 
An Analysis of Covariance (ANCOVA) model will be used to test for a difference 
between treatment arms for the total score. Error! Reference source not found.The
model will include the HIT-6 change from baseline measure at Week 4 as the response 
variable. Baseline value, treatment group and the stratification variables concomitant 
treatment (use vs. no use) and region (North America vs. Rest of World) will be the 
independent variables.
In addition, a similar ANCOVA will be fitted for each individual item.
In the analyses, the value from the week 4 visit will be used, regardless of whether it is an 
actual week 4 assessment or an early termination assessment. In case of any unscheduled 
assessments of HIT-6, the latest post-baseline value will we used.
Change from Baseline in Migraine Treatment Optimization Questionnaire-6 
(mTOQ-6) at Week 4
The migraine treatment optimization questionnaire-6 (mTOQ-6) is a tool used to assess 
response to acute treatment in persons with migraine. The mTOQ-6 is a 6 question, 
Likert-type, self-reporting questionnaire with responses ranging from “Never” to “Half 
The Time Or More” with the following response scores: Never=1, Rarely=2, Less Than 
Half The Time=3, Half The Time Or More=4. The total score for the mTOQ-6 is the sum 
of each response score and will be treated as missing if the response is missing for one or 
more questions. The mTOQ total score ranges from 6 to 24.
The actual score and change from baseline for the total score will be summarized at each 
scheduled visit by treatment group A shift from baseline to the week 4 visit by treatment 
group will be tabulated for each item. 
An ANCOVA model will be used to test for a difference between treatment arms for the 
total score. This model will include the mTOQ-6 change from baseline measure at Week 
4 as the response variable. Baseline value, treatment group and the stratification variables
concomitant treatment (use vs. no use) and region (North America vs. Rest of World) will 
be the independent variables. 
In the analysis, the value from the week 4 visit will be used, regardless of whether it is an 
actual week 4 assessment or an early termination assessment. In case of any unscheduled 
assessments of mTOQ-6, the latest post-baseline value will we used.
Headache Pain Freedom at all Timepoints
The analysis of headache pain freedom (denoted absense of headache pain in section 
2.3.4) at all timepoints other than 2 and 4 hours will be analysed similarly to the key 
secondary endpoint of headache pain freedom described in section 4.3.2.1.3.
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Time to next migraine
Time to next migraine is defined as the first day, beginning from Day 3, at which the 
subject reports a new migraine. The time will be calculated as:
Time to next migraine = Date of new migraine – date of Day 3
and will be censored at the time of the last entry of the subject. 
The analysis of the time to next migraine will be perfomed similarly to the analysis of the 
co-primary endpoints described in section 4.3.1.1.3 as applicable.
PGIC at Week 4
The frequency distribution of PGIC responses will be summarized.
Time to First Rescue Medication
An exploratory analysis will be performed assessing time to first rescue medication. 
Similarly to the primary endpoints, time will be calculated from the start of infusion to 
the first time point post infusion where the patient answers “Yes” to the eDiary question 
“Have you taken any medication(s) to treat your migraine symptom(s) or pain since you 
last entered data in the eDiary?”, using the nominal timepoints for eDiary collection.
Furthermore, the following derivations will apply:

If a patient reports use of rescue medication, the timepoint of first rescue 
medication registration will be used in the analysis (status indicator equals 1, 
indicating rescue medication used)

If a patient does not report any rescue medication use during the 48 hours, the 
timepoint of the last entry in the eDiary for the 48 hours will be used in the 
analysis (status indicator equals 0, indicating administrative censoring)
The analysis will then be conducted similarly to the primary analysis described in section 
4.3.1.1.3. 
4.3.5.
Sensitivity Analyses
The following sensitivity analyses will be performed for each of the three time to event
efficacy endpoints: time to headache pain freedom, time to absence of MBS, and time to 
pain relief. 
Rescue Medication
An analysis similar to the primary analysis will be conducted, where the rescue 
medication censoring is removed. This means that a patient’s time value will be censored 
only if a patient does not report pain freedom/absence of MBS/pain relief at all during the 
48 hours. 
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Persistence
An analysis similar to the primary analysis will be conducted, where an event requires 
that it persists for 30 minutes or longer. This means that a patient reporting pain freedom 
at 2 hours but reports pain again at 2.5 hours will not have an event time of 2 hours but 
will still be at risk of having an event. In these analyses, censoring with respect to first 
rescue medication use still applies. Note that the time between assessments is longer than 
30 minutes after the 4-hour assessment but that the criterion of persisting pain 
freedom/absence of MBS/pain relief requires that the patient reports pain 
freedom/absence of MBS/pain relief at two successive timepoints. 
12 Hours Cut-off
An analysis similar to the primary analysis will be conducted, where only data up to and 
including the 12-hour assessment will be used. Rules for censoring will be the same as 
those used for the primary analysis, except that a time value will be administratively 
censored at 12 hours instead of at 48 hours.  
4 Hours Cut-off
An analysis similar to the primary analysis will be conducted, where only data up to and 
including the 4-hour assessment will be used. Rules for censoring will be the same as 
those used for the primary analysis, except that a time value will be administratively 
censored at 4 hours instead of at 48 hours.  
4.3.6.
Subgroup Analyses for Primary Endpoint
Summaries with descriptive statistics and frequency counts on the co-primary endpoints 
for both dose groups will be provided for the subgroups indicated below. Forest plots will 
also be created for subgroup analyses and will display number of patients, treatment 
differences, SEs, and p-values. The subgroups will be:

Concomitant migraine preventative treatment (use any vs. no use)

Concomitant migraine preventative treatment (use anti-CGRP vs. use others vs. 
no use)

Sex (female vs. male)

Race (black or African American vs. white vs. other)

Age Group (< 65 years vs. ≥ 65 years)

Region (North America vs. Rest of World)

Duration of migraine history at baseline (≤15 yrs, >15 yrs)

Duration of migraine prior to the start of the infusion (< 2 hours vs. 2-4 hours vs. 
> 4 hours)
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
Impact of COVID-19 outbreak (patients randomized before vs. on or after 19
March 2020, with cut-off date selected based on when the impact of COVID-19 
was seen in both the USA and Georgia independently). 
5.
BASELINE, DISPOSITION, AND EXPOSURE
5.1.
Study Day Analysis Window
Study day is defined as:
Study day = date of assessment - date of dosing
Analysis Windows used to report non-diary endpoints are outlined in Table 1.
Table 1
Analysis Windows
Visit
Range
Target Day
Observation used for analysis, if more 
than one exists
Screening
< Day 0
First value
Day 0
Day 0 to Day 7
Day 0
Closest to Target Day
Week 4
> Day 7
Day 28
Closest to Target Day
Note: If two observations exist with same distance to target day, use first observation.
5.2.
Definition of Baseline
The baseline assessment will be the latest available valid measurement taken prior to the 
administration of investigational product.
5.3.
Demographics and Baseline Characteristics
Subject demographic and baseline characteristic information listed as follows will be 
summarized descriptively for the safety population:

Age (years)

Age Group (< 65 years, 65 - 75 years)

Sex (Female, Male)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)

Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander, Other)

Baseline Weight (kg), Height (cm), Baseline BMI (kg/m)

Region (North America, Rest of World)

Concomitant migraine preventative treatment (use, no use)
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Demographics and baseline characteristics will also be presented subgrouped by 
randomization before vs. on or after 19 March 2020, based on the safety population.
In addition, subject listings displaying information about family history and substance use 
(only including patients that actually had substance use) will be produced. 
5.3.1.
Qualifying Migraine Assessment and baseline score
The duration of migraine prior to the start of the infusion, whether or not the patient 
experienced an aura during the qualifying migraine, and answers to the question “What, 
if anything, triggered this migraine” will be summarized in a table by treatment group.
Characteristics of the qualifying migraine for each subject will be listed.
Summaries of the migraine status immediately before infusion will also be provided by 
treatment group. This includes: severity of headache pain, MBS, and whether or not the 
patient had nausea, light sensitivity (photophobia), or sound sensitivity (phonophobia). 
In order to assess the potential impact of the COVID-19 outbreak on the study 
population, migraine status will be presented subgrouped by randomization before vs. on 
or after 19 March 2020.
The summaries and listing will be based on the safety population. 
5.4.
Subject Disposition
The number of subjects randomized, treated, had an incomplete infusion, and terminated 
from the clinical trial early will be summarized. The reason for early discontinuation 
from the clinical trial will be summarized. Subjects randomized but not included in the 
full analysis population and the reasons for exclusion will be summarized. The number of 
subjects screened and summary of screen failure reasons will also be summarized. 
Additionally, the summary of subjects present at each visit will be summarized. 
A listing of entry criteria that were not met will be produced.
The number of patients randomized and the number of patients withdrawn from the 
study, including reason for the withdrawal, before and after 19 March 2020, will be 
summarized in order to assess the impact of the COVID-19 outbreak.
In addition, the visits will be tabulated by type of visit (onsite or remotely) and treatment 
group based on the safety population, to assess the potential impact of the COVID-19 
outbreak on the visit structure.
The number of subjects in each analysis population will be summarized.
5.5.
Prior and Concomitant Medications
Each medication will be recorded as prior, concomitant, or both prior and concomitant:
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
Prior only: Medications with a stop date before the treatment dosing date will be 
considered prior medications. 

Concomitant only: Medications with a start date on or after the treatment dosing 
date will be considered concomitant medications. 

Prior and Concomitant: Medications with a start date before the treatment dosing 
date and continued past treatment dosing date (with a stop date after the treatment 
dosing date, or ongoing) will be considered prior and concomitant medications.
A medication with an incomplete stop date will be considered concomitant if:

Month is missing, and year is equal to or after the year of the infusion date, or

Day is missing, and year is equal to the year of the infusion date and month is 
equal to or after the month of the infusion date.
A tabular summary of concomitant medications by drug class and generic name will be 
provided for the most frequently used concomitant medications (defined as being 
reported for 10% or more of eptinezumab subjects) for the safety population. A listing
displaying all concomitant medications will be provided for the safety population. In the 
data listing, each medication will be recorded as prior, concomitant, or both prior and 
concomitant.  
The headache medications recorded in the eDiary will not be integrated with the 
concomitant medications as these two data capture tools have distinctly different format, 
purpose and functionality. These diary-based results will be summarized in a separate 
output. For these, the percent of days that subjects used headache medication will be 
summarized by treatment group. The following type of medication in eDiary will be used 
for summary: Triptans, Nausea medication, Sleep medication, NSAIDs, Analgesics, 
Opioids, Medical device.
5.6.
Medical History
Medical history will be coded using MedDRA version 20.1. Medical History will be 
tabulated for the safety population by system organ class, preferred terms and treatment 
group.
5.7.
Migraine History
Migraine history including age at diagnosis, the average number of headache/migraine 
days per 28-day period in the 3 months prior to screening, whether the patient suffers 
from aura, migraine attacks’ association to headache of moderate to severe intensity and a 
most bothersome symptom of nausea, photophobia, or phonophobia, number of years that
the patient has suffered from migraines as well as migraine symptoms (answer to 
“Migraines can be brought on by”) will be summarized in a table by treatment group for 
the safety population. 
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5.8.
Study Drug Exposure
Study drug exposure will be summarized for the safety population with descriptive 
statistics for the following variables by treatment groups:

Number and percent of subjects who received treatment after randomization

Number and percent of subjects with dose interruption

Number and percent of subjects who were in the study for 0, 1, 2, 3, 4, and > 4 
weeks after infusion as well as descriptive statistics for number of days spent 
in the study after infusion

Exposure time (end of infusion time – initiation of infusion time)
A listing of subjects who had dose interrupted will be provided. 
5.9.
eDiary Compliance
Patients have scheduled eDiary assessments at the following 14 time points: 
just before infusion, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 9, 12, 24, and 48 hours. The missing
rate at each time point will be summarized descriptively based on the safety population.
6.
ANALYSIS OF SAFETY ENDPOINTS
6.1.
Adverse Events
Adverse events are collected from the time of informed consent through the final subject 
visit. A treatment-emergent adverse event (TEAE) is an adverse event with a start date 
and time on or after the date and time of the infusion. Only TEAEs will be included in 
summary tables.
Verbatim descriptions of adverse events will be mapped to the Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and converted to the same version 
(version 20.1). All adverse events are assessed by the investigator using five severity 
grades. AEs are also determined by the investigator to be related or not related to study 
drug. 
For the purpose of inclusion in TEAE tables, incomplete AE onset and end dates will be 
imputed as specified below. No duration will be calculated for adverse events with 
incomplete start-or stop dates, or for ongoing adverse events.
Imputation rules:

Missing onset day (where UK and UKN indicate unknown or missing day and 
month respectively) UK-MMM-YYYY: 
o
If the month and year are different from the month and year of the 
infusion, assume 01-MMM-YYYY;
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o
If the month and year are the same as the infusion month and year, and the 
end date (after any imputation) is on or after the infusion, then assume the 
date of the infusion;
o
If the month and year are the same as the infusion and the end date (after 
any imputation) is prior to the infusion, then assume the end date for the 
onset date.

Missing onset month DD-UKN-YYYY/UK-UKN-YYYY: 
o
If the year is different from the year of the infusion, assume 01-JAN-
YYYY of the collected year;
o
If the year is the same as the infusion, and the end date (after any 
imputation) is on or after the infusion, then assume the date of the 
infusion;
o
If the year is the same as the infusion, and the end date (after any 
imputation) is prior to the infusion, then assume the end date for the onset 
date.

Missing end dates:
o
UK-MMM-YYYY: assume the last day of the month;
o
DD-UKN-YYYY/UK-UKN-YYYY: assume DD-DEC-YYYY/31-DEC-
YYYY.
Tables by preferred term (PT) and tables by system organ class (SOC) and preferred term 
will be sorted in descending order by the percentage of patients in the eptinezumab 100 
mg treatment group.
For the safety population, the following tabular summaries will be created:

An overall summary of TEAEs will present the number and percentage of 
subjects with at least 1 reported TEAE, study drug related TEAE, serious TEAE, 
study drug infusion interruption, and death

TEAEs by SOC and preferred term

TEAEs by SOC, preferred term, and maximum severity

Study drug related TEAEs by SOC and preferred term

TEAEs by preferred term

TEAEs that led to study drug infusion interruption by SOC and preferred term

TEAEs that led to early withdrawal from study

Serious TEAEs by SOC and preferred term
For incidence reporting, if a subject reported more than 1 AE that was coded to the same 
preferred term/system organ class, the subject will be counted only once for that specific 
preferred term/system organ class. For TEAEs presented by severity, the worst severity 
for each event during the clinical trial will be presented for each subject. If the severity is 
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missing for a TEAE, then a severity of “Severe” (Grade 3) will be assigned. The imputed 
values for severity assessment will be used for incidence summaries, while the actual 
values will be used in data listings.
For TEAEs presented by relationship to study drug, the closest relationship to study drug 
for each event during the clinical trial will be presented for each subject. If the 
relationship to investigational product is missing for a TEAE, a causality of “Related” 
will be assigned. The imputed values for relationship assessment will be used for 
incidence summaries, while the actual values will be presented in data listings.
All AEs, SAEs, TEAEs leading to study drug infusion interruption, SAEs leading to 
death and Grade 4 or higher AEs will be displayed in separate listings. In case of any 
deaths in the study, all adverse events for patients who died will be listed. 
The listings will include Subject ID, actual treatment received, SOC, preferred term, 
investigator term, start and stop date of the AE, whether or not the AE was treatment 
emergent, duration, frequency (pattern), severity, relatedness, action taken, outcome, and 
seriousness of the AE. Imputed start or stop dates will not be displayed in listings of AEs.
6.1.1.
Adverse events of special interest
Adverse events of special interest include the following.
Hypersensitivity and Anaphylactic Events
The subset of adverse events with a MedDRA coded SOC of Immune system disorders 
and PTs of Hypersensitivity, Anaphylactic reaction and Anaphylactoid reaction.
Events Associated with Suicide
The subset of adverse events with a MedDRA coded SOC of Psychiatric disorders and 
PTs of Depression suicidal, Intentional self-injury, Suicidal behavior, Suicidal ideation, 
Suicide attempt and Self injurious behavior.
Cardiovascular Events
The subset of adverse events with

A MedDRA coded SOC of Cardiac disorders and PTs of Atrial fibrillation, 
Bradycardia, chest pressure, Palpitations, Sinus bradycardia, Sinus 
tachycardia and Tachycardia, or

a MedDRA coded SOC of Investigations and PTs of Blood pressure increase, 
Blood pressure systolic increase, Elevated blood pressure, Heart rate 
increased, Heart rate decreased, Heart rate irregular, Electrocardiogram 
abnormal, Electrocardiogram Q wave abnormal, Electrocardiogram QT 
interval abnormal, and Electrocardiogram QT prolonged, or

a MedDRA coded SOC of Nervous system disorders and PTs of Syncope, or
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
a MedDRA coded SOC of Vascular disorders and PTs of Flushing, Hot flush, 
Hypertension, Hypotension, Ischemia, and Prehypertension, or

a MedDRA coded SOC of General disorders and administration site 
conditions and PTs of Chest pain and Feeling hot.
Nervous System Events
The subset of adverse events with a MedDRA coded SOC of Nervous system disorders 
and PTs of Seizure. 
Hepatic Events
A subset of adverse events with a MedDRA coded SOC of Investigations and PTs of 
Alanine minotransferase increased, Aspartate aminotransferase increased, Blood bilirubin 
increased, Hepatic enzyme increased, Liver function test abnormal, Liver function test 
increased, and Transaminases increased.
Events Associated with Study Drug Infusion
A subset of adverse events withing one week of dosing with

a MedDRA coded SOC of Skin and subcutaneous tissue disorders and PTs of 
Dermatitis bullous, Pruritus, Pruritus allergic, Pruritus generalized, Rash, 
Rash erythematous, Rash generalized, Rash macular, Rash macularpapular, 
Rash papular, Rash pruritic, Swelling face, and Urticaria, or

a MedDRA coded SOC of General disorders and administration site 
conditions and PTs of Infusion site discomfort, Infusion site eczema, Infusion 
site erythema, Infusion site extravasation, Infusion site nerve damage,
Infusion site pain, Infusion site paresthesia, Infusion site pruritus, Infusion site 
rash, Infusion site reaction, Infusion site swelling, and Injection site 
paraesthesia, or

a MedDRA coded SOC of Gastrointestinal disorders and PTs of Lip oedema, 
Oral pruritus, and Paraesthesia oral, or

a MedDRA coded SOC of Respiratory, thoracic and mediastinal disorders and 
PTs of  Choking sensation, Cough, Dyspnoea, Nasal congestion, 
Oropharyngeal pain, Rhinitis allergic, Rhinorrhoea, Sinus congestion, 
Sneezing, Throat irritation, and Wheezing. 
Adverse Events of Interest Analysis
The adverse events of special interest (AESI) will be summarized and listed in the 
following categories:

AESIs by system organ class and preferred term.

AESIs by system organ class, preferred term, and maximum severity
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
AESIs by system organ class, preferred term, and relationship to study drug.

AESIs that lead to infusion interruption by system organ and preferred term

AESIs with action taken of study drug discontinuation by system organ class 
and preferred term

AESIs assessed as serious by system organ class and preferred term
6.2.
Clinical Laboratory Evaluations
The clinical safety laboratory test values will be presented either in conventional or 
Système International (SI) units. 
The potentially clinically significant (PCS) criteria used for the clinical safety laboratory 
tests are the Lundbeck standard PCS criteria described in SOP_09978: PV – PCS and 
standard reference values for laboratory investigations, vital signs and ECGs in clinical 
studies, version 6, and are also included in Table 4.
Descriptive statistics for the laboratory parameters, both absolute values and changes 
from baseline, will be presented by test and scheduled visit and the last assessment. All 
available post baseline assessments will be included in the identification of the last 
assessment.
Low, normal, and high classifications will be applied to determine whether the laboratory 
test value was below (low), within (normal), or above (high) the reference range for that 
test. The number and percentage of subjects with shifts in their results from classification 
of baseline (low, normal, high) to classification of the minimum/maximum post-baseline 
(low, normal, high) will be presented.
The number and percentage of patients 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.
For patients with post-baseline PCS values, listings will be provided including all 
available values for the variable, with flagging of PCS values and out-of-reference-range 
values.
All the adverse events in patients with post-baseline PCS values will be listed by 
treatment group and patient ID; the listings will include all available values for the 
variable with flagging of PCS values and out-of-reference-range values, 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.
Due to the COVID-19 outbreak, local laboratories rather than the planned centralized 
laboratory have been used at some sites in Georgia. Data from the local laboratories will 
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be included in the ADaM datasets, but only normal ranges from the laboratory and PCS 
range classifications will be used in the analyses. Thus, the absolute values and the 
change from baseline values from local laboratories will be excluded from summary 
statistics, but included in any listings, if relevant.
If a visit was performed remotely, study procedures such as collection of blood samples 
for laboratory analyses, unscheduled visits may have been performed with extended visit 
window up to three weeks after the planned Week 4 visit. In such cases, the statistical 
analysis of Week 4 values will include the unscheduled visit.
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6.2.1.
Potential Drug-induced Liver Injury (DILI)
Liver function test data will also be provided in separate listings for:

Subjects who possibly met Hy’s Law criteria (ie, had any elevated ALT or AST 
of >3xULN, and increase in total bilirubin >=2xULN, and ALP <2xULN at the 
same visit)

Subjects who met any one or more of the following criteria at any post-baseline 
visit (list laboratory parameters ALT, AST, ALP and total bilirubin only)
o
Either ALT or AST or both >2x, >3x, >5x, >10x, or >20xULN
o
ALP >1.5xULN
o
Total bilirubin >2xULN

Subjects who had any elevated ALT or AST of >3xULN, and an increase in total 
bilirubin >1.5xULN at the same visit
A summary table will also be provided for number of subjects who met any of the criteria 
specified above at any post-baseline visit.
Data from local laboratories will be included in the DILI classification.
6.3.
Vital Signs
The PCS criteria used for vital signs are the Lundbeck standard PCS criteria described in 
SOP_09978: PV – PCS and standard reference values for laboratory investigations, vital 
signs and ECGs in clinical studies, version 6, and are also included in Table 5.
The number and percentage of patients 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.
For patients with post-baseline PCS values, listings will be provided including all 
available values for the variable, with flagging of PCS values and out-of-reference-range 
values.
All the adverse events in patients with post-baseline PCS values will be listed by 
treatment group and patient ID; the listings will include all available values for the 
variable with flagging of PCS values and out-of-reference-range values, 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.
The observed data at baseline and change from baseline for each measurement day and 
last assessment will be summarized for each parameter with descriptive statistics. All 
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available post baseline assessments will be included in the identification of the last 
assessment.
6.4.
Electrocardiogram Results
Results for each ECG parameter will be summarized by treatment group at each visit and 
last assessment for the observed data and for changes from baseline. All available post 
baseline assessments will be included in the identification of the last assessment.
The overall ECG assessment as determined by the investigator will be reported as 
“Normal” or “Abnormal – not clinically significant”, or “Abnormal – clinically 
significant” and summarized by visit and across visits. A shift table of overall ECG 
assessment from baseline to the most extreme post-baseline value will be presented.
Additionally, the highest post-baseline value for QTc interval (using Fridericia’s 
correction) will be summarized descriptively as a categorical variable. Each QTcF value 
for a given subject will be grouped into 3 categories:

QTcF interval 450 - 480 msec

QTcF interval > 480 - 500 msec

QTcF interval > 500 msec
The largest post-baseline change in QTcF measures will also be analyzed as categorical 
variables. The change in QTcF in a given subject will be grouped into 2 categories:

QTcF interval increases from baseline > 30 msec

QTcF interval increases from baseline > 60 msec
Relevant ECG data will also be displayed in separate listings for:

Subjects who shifted from normal or abnormal not clinically significant at 
baseline to abnormal clinically significant during the treatment period

Subjects who had an abnormal clinically significant assessment at any time during 
the study

Subjects who ever had a QTcF interval increase from baseline > 30 msec during 
the treatment period

Subjects who ever had any value of QTcF interval >= 450 msec at any visit
The PCS criteria used for ECG parameters are the Lundbeck standard PCS criteria 
described in SOP_09978: PV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studies, version 6, and are also included 
in Table 6. 
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The number and percentage of patients 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.
For patients with post-baseline PCS values, listings will be provided including all 
available values for the variable, with flagging of PCS values and out-of-reference-range 
values.
All the adverse events in patients with post-baseline PCS values will be listed by 
treatment group and patient ID; the listings will include all available values for the 
variable with flagging of PCS values and out-of-reference-range values, 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.
6.5.
Columbia-Suicide Severity Rating Scale (C-SSRS)
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a patient questionnaire that 
evaluates suicidal ideation and behaviors. In this study, the C-SSRS is assessed at 
screening using the “Baseline/Screening Version” and at subsequent timepoints using the 
“Since Last Visit” version. The screening assessment will assess suicidal ideation during 
the past 6 months and suicidal behaviour during the past 5 years. The results (yes/no) 
from the 5 questions under suicidal ideation and the 5 questions under suicidal behavior 
will be summarized at screening (using the answers to the Baseline/Screening version)
and post baseline using percentages and counts. The denominator for percentages will be 
the number of subjects with a C-SSRS assessment in the relevant period that is, for the 
screening assessments it will equal the number of patients with a C-SSRS assessment at 
screening, and for post-baseline assessments it will equal the number of patients with a 
C-SSRS assessment at any time post baseline. The summaries will also include answers 
to “Has the subject engaged in Non-Suicidal Self-Injurious Behaviour?”. The post-
baseline by-question summary will list a subject as "yes" if they selected yes at any time 
after baseline.
For patients with any post-baseline suicidal behavior, if any, listings will be prepared 
including all C-SSRS scores for these patients.
6.6.
Pregnancies
Any reported positive pregnancy results or reported pregnancies will be listed.
6.7.
Other
Emergency room visits and procedures will be listed for any patients with an emergency 
room visit due to migraine during the study.
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7.
CHANGES TO ANALYSES SPECIFIED IN THE 
PROTOCOL
The use of the logrank test for assessing the effect of treatment with eptinezumab has 
been removed. In order to account for the stratification, the effect of treatment will be 
assessed using the likelihood ratio test from the stratified Cox model, which is also used 
for estimating the treatment effect.
In the study protocol an exploratory endpoint denoted “Pain relapse when the subject was 
headache pain-free at 2 hours” is included. However, it is expected that the analyses of 
sustained pain freedom through 24 and 48 hours endpoints will provide sufficient insight 
into this matter, and therefore no analysis of the specific pain relapse endpoint will be 
included.
An analysis of time to rescue medication use has been added as an exploratory analysis 
and will be analysed using the same methodogy as for the co-primary endpoints.
A number of sensitivity analyses has been added.
The secondary endpoints have been redefined due to comments made by the FDA to the 
previous version of the SAP. The testing strategy for secondary endpoints has been 
changed from an alpha-sharing strategy to a hierarchical strategy.
Analyses have been added in order to assess the potential impact of the COVID-19 
outbreak.
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8.
APPENDIX I
Table 2
Schedule of Events and Assessments
Assessment
Screening Period
(Day -56 to Day -1)
Rand/
Dosing Day
End of Study/Early 
Term
(Day 28 ± 3)
Screening 
Visit
Weekly Contact 
7
Day 0 Visit
Week 4 Visit
Informed Consent 
X
Inclusion/Exclusion Criteria1
X
X
Demographics
X
Medical History (including family and social history)
X
Height, Weight and BMI2
X
X
X
Physical Exam
X
X
Vital Signs3
X
X
X
eDiary Training1
X
X
eDiary Completion4
X
Migraine History
X
Qualifying Migraine Assessment1
X
HIT-6
X 
X
mTOQ-6
X
X
PGIC
X
C-SSRS5
X
X
X
12-lead ECG
X
X
Hematology/Chemistry1
X
X
X
Serology (HIV/Hepatitis B and C)
X
Urine Drug Screen1
X
X
Urine Pregnancy (hCG) Test1
X
X
X
AE Review1,6
X
X
X
X
Concomitant Medication Review1,6
X
X
X
X
Randomization1
X
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Eptinezumab/placebo administration
X
1 Prior to dosing on Dosing Day
2Height and BMI only collected at Screening visit. Weight collected at Screening, Day 0 and Week 4 visits. 
3 On Day 0, vital signs should be collected pre-dose and any time prior to the subject leaving the site post-dose.
4 An electronic diary (eDiary) will be assigned before dosing on the Day 0 visit to collect migraine data pre-dose through 48 hours. Additionally, subjects will 
complete eDiary data entry from Day 3 until a new migraine is reported. 
5 C-SSRS “Baseline/Screening Version” should be used at the screening visit and C-SSRS “Since Last Visit Version” should be used at all subsequent 
timepoints. Complete C-SSRS at Screening, Week 4 and, if applicable, the weekly contact after the subject has been in screening for 4 weeks. If the screening 
period exceeds 28 days, the C-SSRS “Since Last Visit Version” should be completed via a phone call to the subject on Screening Day 29 (+7 days).
6 If the screening period exceeds 28 days, AEs and concomitant medications should be reviewed via a phone call to the subject on Screening Day 29 (+7 days).
7 Weekly contact attempts will occur in which updates are obtained from the subject via a mobile application or a phone call from the site staff to check in with 
the subject during the screening period.
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Table 3
Schedule of Events and Assessments for Day 0 through 48 Hours 
Assessment
Pre-
dose
Dos
e
Post Start of Infusion
Start of 
Infusio
n
0.5 
hr 
(+20 
min)
1 hr 
(+20 
min)
1.5 
hr 
(+20 
min)
2 hr 
(+20 
mins
2.5 
hr
(+20 
min)
3 hr 
(+20 
min)
3.5 
hr 
(+20 
mins
)
4 hr 
(+2 
hr)
6 hr 
(+3 
hr)
9 hr 
(+3 
hr)
12 hr 
(+12 
hr)
24 hr 
(+12 
hr)
48 hr 
(+12 
hr)
Inclusion/Exclusion 
Criteria
X
eDiary Training
X
eDiary Completion1
X
X3
X
X
X
X
X
X
X
X
X
X
X
X
X
Qualifying Migraine 
Assessment
X
Vital Signs2
X
X
Hematology/Chemist
ry
X
Urine Drug Screen
X
Urine Pregnancy 
(hCG) Test
X
Adverse Event 
Review
X
Concomitant 
Medication Review
X
Randomization
X
Eptinezumab/place
bo administration
X
1 An electronic diary (eDiary) will be assigned before dosing on the Day 0 visit to collect migraine data. eDiary will be completed by the subject. While the 
subject is in the clinic the study staff will provide close oversight to ensure subject completes eDiary at all timepoints, as close to the beginning of the window as 
possible.
2 On Day 0, vital signs should be collected pre-dose and any time prior to the subject leaving the site post-dose.
3 Immediately when the infusion is started, the subject will be required to press a button on the eDiary device to indicate that the infusion has started.
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Note: Timepoint windows only pertain to subject completion of eDiary.
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9.
APPENDIX II
9.1.
SAS® Code
The SAS® code displayed below performs the analyses described in sections 4.3.1 and 4.3.2 for 
analyzing the co-primary and key secondary endpoints. 
For the time-to-event endpoints, it is assumed that a dataset containing one record per patient is 
available. TIME represents the time from start of infusion to the endpoint (e.g. time to headache 
pain freedom), STATUS represents whether or not an event was observed i.e. in the case of 
headache pain freedom, STATUS = 1 indicates that headache pain freedom was acheived at the 
timepoint given by TIME and STATUS = 0 indicates that headache pain freedom was not 
acheived (censored observation). REGION represents the regional stratification factor (North 
America vs. Rest of World), CONMED represents the stratification factor for concomitant 
preventive treatment (use vs. no use), and TREAT represents the treatment received in the study. 
For the binary endpoints the treatment and stratification variables are the same as described 
above. For these analyses, RESPONDER represents whether or not the endpoint was achieved for 
the patient – for instance when considering 2-hour headache pain freedom, RESPONDER = “Y” 
indicates that the patient experienced headache pain freedom at the 2-hour timepoint with the 
absence of rescue medication and RESPONDER = “N” indicates that the patient did not 
experience headache pain freedom at the 2-hour timepoint. 
9.1.1.
Cox proportional hazards model
The stratified Cox proportional hazards model with Efron’s method of tie handling with a single 
treatment covariate will be fitted using the following code. The values for obtaining median 
estimates for each treatment group are saved in the dataset “survdat”. From “survdat” the values 
can be averaged across strata with weights according to the description in section 4.3.1 to obtain 
median estimates for each treatment group:
proc phreg data = xxx;
    class TREAT (ref = ‘PBO’);
    strata REGION CONMED;
    model TIME * STATUS(0) = TREAT / ties = EFRON; 
    hazardratio TREAT / cl = pl;
   baseline out = survdat survival = survival / group = TREAT diradj;
run;
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9.1.2.
Cochran-Mantel-Haenszel test
The Cochran-Mantel-Haenszel test adjusting for the study’s stratification factors and computation 
of the odds ratio, as well as the computation of difference in rates and associated Wald 
confidence intervals not taking the stratification into account, will be performed using the code
given below. For stratified 2x2 tables all three of the CMH statistics test the same hypothesis.
proc freq data = xxx;
   tables REGION*CONMED*TREAT*RESPONDER / cmh;
   tables TREAT*RESPONDER / riskdiff (CL=(WALD));
run;
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10.
APPENDIX III
Table 4
PCS Criteria for Clinical Safety Laboratory Tests
Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
Haematology / Coagulation
B-haemoglobin
HGB
g/dL
≤ 9.5 (women)
≥ 16.5 (women)
≤ 11.5 (men)
≥ 18.5 (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
IU/L
≥ 3 × ULN
S-alanine aminotransferase
ALT
IU/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
IU/L
≥ 3 × ULN
S-gamma glutamyl transferase
GGT
IU/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)
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Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
≥ 630 (men)
Electrolytes
S-sodium (natrium)
SODIUM
mmol/L
≤ 125
≥ 155
S-potassium (kalium)
K
mmol/L
≤ 3.0
≥ 6.0
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
%
≥ 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
IU/L
≥ 400 (women)
≥ 750 (men)
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Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
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
Urine
Urinary pH
PH
≤ 4
≥ 9
S=serum; B=whole blood; U=urine
Table 5
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.
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Table 6
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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H. Lundbeck A/S
18903A Statistical Analysis Plan
04AUG2020 Version 3.0
CONFIDENTIAL
Page 48 of 48
11.
REFERENCES
1.
ICH. ICH Harmonised Guideline E9 (R1): Addendum on estimands and sensitivity analysis in 
clinical trials to the guideline on statistical principles for clinical trials. November 2019.
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