Conditions: Cluster Headache, Episodic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 231
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of eptinezumab in participants with episodic Cluster Headache (eCH)

Detailed description:
Eligible participants will be randomly assigned to receive treatment, in a blinded manner, two infusions of either eptinezumab or placebo in a cross-over manner during the Placebo-controlled Period and Active Treatment Period of the study.

The total duration of the study after randomization is 24 weeks, including a safety follow-up period of 8 weeks.

Arms:
arm 1: Eptinezumab in the Placebo-controlled Period, followed by administration of placebo in the Active Treatment Period arm 2: Placebo in the Placebo-controlled Period, followed by administration of eptinezumab in the Active Treatment Period

Interventions: intervention 1: Eptinezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Eptinezumab - concentrate for solution for infusion, intravenously intervention 2: Placebo - 100 milliliters (mL) of 0.9% normal saline, intravenously

Protocol document:
Prot_000.pdf: 
H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 1 of 112
Clinical Study Protocol
Interventional, randomized, double-blind, parallel-group, 
placebo-controlled delayed-start study to evaluate the efficacy and 
safety of eptinezumab in patients with episodic Cluster Headache
Eptinezumab
Study No.:
19386A (Alleviate)
EudraCT/IND No.:
2020-001969-37 / 151358
Sponsor:
H. Lundbeck A/S (Lundbeck)
2500 Valby (Copenhagen), Denmark
Edition No.:
5.0 (includes all changes since Edition 4.0)
(the version No. in the footer is the system version No.)
Date of edition:
03 April 2023
Edition history:
Edition 1.0 (original protocol), 25 September 2020
Edition 2.0, 05 May 2021
Edition 3.0, 17 January 2022
Edition 4.0, 30 Aug 2022
This document is the property of H. Lundbeck A/S and H. Lundbeck A/S is the holder of any and all 
related intellectual property rights, including, but not limited to, copyrights. This document is 
confidential. It is not to be copied or distributed to other parties without prior written authorization 
from H. Lundbeck A/S.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704
NCT04688775


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 2 of 112
Synopsis – Study 19386A
Sponsor
H. Lundbeck A/S
Investigational Medicinal Product
Eptinezumab
Study Title
Interventional, randomized, double-blind, parallel-group, placebo-controlled delayed-start study to evaluate the 
efficacy and safety of eptinezumab in patients with episodic Cluster Headache (eCH)
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To evaluate the efficacy of eptinezumab in 
patients with eCH
Primary endpoint:
Change from Baseline in the number of weekly attacks 
(Weeks 1–2)
Key secondary endpoints:
Response: ≥50% reduction from Baseline in the number of 
weekly attacks (Weeks 1-2)
Change from Baseline in the number of weekly times an 
abortive medication was used (Weeks 1-2) 
Change from Baseline in the number of daily attacks 
(Days 1-3)
Change from Baseline in the number of weekly days with 
< 3 attacks per day (Weeks 1-2)
Time from first infusion of IMP to resolution of cluster 
headache bout (within the first 4 weeks)
Number of attacks starting <= 24 hours after the start of the 
first infusion of IMP
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 3 of 112
Primary Objective (continued)
To evaluate the efficacy of eptinezumab in 
patients with eCH
Secondary endpoints: 
Change from Baseline in the daily mean score on 5-point 
self-rating pain severity scale (Days 1- 3)
Change from Baseline in the number of weekly attacks 
(Week 1)
Change from Baseline in the number of weekly attacks 
(Week 2)
Response: 50% reduction from Baseline in the number of 
weekly attacks (Week 1)
Response: 30% reduction from Baseline in the number of 
weekly attacks (Week 1)
Response: 30% reduction from Baseline in the number of 
weekly attacks (Weeks 1-2)
Change from Baseline in the weekly integrated measure of 
frequency and intensity of pain (Weeks 1-2) (that is, the sum 
of the intensity (worst pain on a 5-point self-rating pain 
severity scale) for each attack during that week).
Change from Baseline in the weekly integrated measure of 
frequency and intensity of pain (Week 1) (that is, the sum of 
the intensity (worst pain on a 5-point self-rating pain 
severity scale) for each attack during that week).
Change from Baseline in the weekly integrated measure of 
frequency and intensity of pain (Week 2) (that is, the sum of 
the intensity (worst pain on a 5-point self-rating pain 
severity scale) for each attack during that week).
Change from Baseline in the number of weekly attacks 
(Weeks 1-4)
Change from Baseline in the weekly integrated measure of 
frequency and intensity of pain (Weeks 1-4) (that is, the sum 
of the intensity (worst pain on a 5-point self-rating pain 
severity scale) for each attack during that week).
Change from Baseline in the mean score on 5-point self-
rating pain severity scale (average per attack over a week) 
for each of Weeks 1, 2, 3, and 4
Change from Baseline in the number of weekly attacks for 
each of Weeks 3 and 4
Patient Global Impression of Change (PGIC) score at each 
of Weeks 1, 2, and 4 
Change from Baseline in the Sleep Impact Scale (SIS) 
domain scores at each of Weeks 2 and 4 
Exploratory endpoints:
Response: 75% reduction from Baseline in the number of 
weekly attacks (Weeks 1-2)
Change from Baseline in the number of weekly times an 
abortive medication was used (Weeks 1-4)
Time from first infusion of eptinezumab to resolution of 
cluster headache bout (within the first 16 weeks; only for 
patients randomized to eptinezumab at Baseline) 
Use (yes/no) of abortive medication (triptans or O2) for each 
of Weeks 5 to16
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 4 of 112
Use (yes/no) of preventive medication for each of Weeks 1 
to 16
Use (yes/no) of transitional treatment for each of Weeks 5 to 
16 
Number of attacks starting <= 24 hours after the start of the 
first infusion of IMP divided into three parts: one for attacks 
starting  > 0 and <= 8  hours after the start of the first 
infusion of IMP, one for attacks starting >8 and <=16 hours 
after the start of the first infusion of IMP, and one for 
attacks starting >16 and <=24 hours after the start of the first 
infusion of IMP
Change from Baseline in the EQ-5D-5L Visual Analogue 
Scale (VAS) score at Weeks 8 and 16 
Patient Global Impression of Change (PGIC) score at Weeks 
8 and 16 
Number of weekly attacks for each of Weeks 5 to 16
Severity of pain (average per attack over a week) based on a 
5-point self-rating pain severity scale for each of Weeks 5 to 
16
Estimands to Address the Primary Objective
Estimand for the primary endpoint:
The primary estimand will be the mean difference in change from Baseline in the number of weekly attacks 
(Weeks 1-2) between patients with episodic cluster headache treated with eptinezumab and placebo, without 
use of transitional treatment, and regardless of use of abortive or preventive medication, and infusion 
interruption or termination before full dose is received.
Secondary Objectives
To evaluate the efficacy of eptinezumab on 
health-related quality of life, health care 
resource utilization, and work productivity 
Secondary endpoints: 
Change from Baseline in EQ-5D-5L Visual Analogue Scale 
(VAS) at Weeks 2 and 4
Health Care Resources Utilization (HCRU) at Baseline and 
Week 4
Change from Baseline in the Work Productivity Activity 
Questionnaire: General Health second version 
(WPAI:GH2.0) sub-scores (Absenteeism, Presenteeism, 
Work productivity loss, Activity impairment) at Week 4
Safety Objectives
To evaluate the safety and tolerability of 
eptinezumab
Safety Endpoints:
Adverse events
Absolute values and changes from baseline in clinical safety 
laboratory test values, vital signs, weight, and ECG 
parameter values
Potentially clinically significant clinical safety laboratory 
test values, vital signs, weight changes, and ECG parameter 
values
Development of specific anti-eptinezumab antibodies 
(ADA) including neutralizing antibodies (NAbs)
Columbia-Suicide Severity Rating Scale (C-SSRS) score
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 5 of 112
Study Methodology
This is an interventional, multi-regional, randomized, double-blind, placebo-controlled delayed-start study, 
designed to demonstrate the efficacy and safety of eptinezumab in patients with episodic Cluster Headache 
(eCH).
The target population for this study is defined as patients with eCH, based on the IHS ICHD-3 classification, 
with an adequately documented record or reliable history of eCH prior to Screening Visit 1 and confirmed via 
prospectively collected information in the eDiary during Screening Period 2. The study is planned as a global 
study. 
304 patients will be randomly allocated via a randomization system to one of the two initial treatments: 
eptinezumab 400 mg, or placebo, in a ratio of 1:1.
The total study duration from Screening Visit 1 to the Safety Follow-up Visit is approximately 77 weeks and 
includes Screening Period 1 (approximately 12 months / 52 weeks), Screening Period 2 (7 days), a Placebo-
controlled Period (4 weeks), an Active Treatment Period (4 weeks), a Post-treatment Observational Period 
(8 weeks), and a Safety Follow-up Period (8 weeks).
The patients can be screened up to 12 months prior to Screening Period 2. 
The patients will enter Screening Period 2 as soon as possible after they experience the beginning of a cluster 
headache bout, which is characterized by the presence of at least one typical cluster headache attack, and not 
later than 1 week after the start of the first attack. Under exceptional circumstances, when a patient is able to 
attend Screening Visit 2 only during the second week after the first typical cluster headache attack, the 
possibility to enroll this patient in the study will be discussed with the investigator and the decision will be 
taken in the context of known history of typical duration of the bout for the individual patient.
Repeat of Screening Visit 1 and Screening Visit 2 will be allowed for patients who do not meet pre-defined 
specific eligibility criteria (details are presented in the study protocol).
Eligible patients will be randomly assigned to receive at the Baseline Visit (Day 0/Visit 3) either eptinezumab 
400 mg or placebo, administered as an IV infusion over 45 minutes (+15 minutes). Preferably the infusion 
should be administered in the morning. 
All patients will continue in the Active Treatment Period of the study and will receive a second IMP infusion 
(eptinezumab 400 mg or placebo), administered over 45 minutes (+15 minutes), at the end of Week 4 (Visit 6) 
in a blinded manner, so that patients previously exposed to eptinezumab will receive placebo and patients 
randomized to placebo will receive eptinezumab 400 mg. 
The Safety Follow-up Visit will take place at Week 24 (Visit 10), 20 weeks (5 half-lives) after the second 
IMP administration. 
Patients who withdraw from the study, except for those who withdraw their consent, will be asked to attend a 
Withdrawal Visit as soon as possible and a further Safety Follow-Up Visit (SFU), scheduled 20 weeks after 
the last IMP administration.
Eligibility will be assessed during Screening Period 1, during Screening Period 2, as well as before the 
administration of IMP at the Baseline Visit (Day 0/Visit 3). 
Study visits:
The following visits will be site visits: Screening Visit 1, Screening Visit 2, Baseline Visit (First Visit of 
the Placebo-controlled Period (Day 0/Visit 3) (randomization and IMP infusion)), Last Visit of the 
Placebo-controlled Period at the end of Week 4 (Visit 6 - second IMP infusion), Completion Visit at 
Week 16 (Visit 9) and SFU visit at Week 24 (Visit 10) or Withdrawal Visit, if applicable. 
All other study visits will be phone contact visits. 
In exceptional situations, such as where COVID-19 pandemic restrictions impact the ability to perform site 
visits, site visits may only consist of blood sampling and urine sampling (for clinical laboratory tests, 
exploratory eptinezumab quantification, ADA including Nab, and exploratory biomarkers), and ECG, vital 
signs, physical and neurological examinations, adverse event recording, and IMP administration, while the 
remaining assessments (eDiary, ePROs, C-SSRS, and investigator evaluations) can be conducted remotely via 
a virtual clinic visit. These cases must be approved by the CRO’s Medical Monitor.
Patients will be assigned an eDiary at the Screening Visit 2 and will be required to complete this daily from 
the time of Screening Visit 2 until the Completion Visit (Week 16/Visit 9) or until the Withdrawal Visit.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 6 of 112
During the study visits with IMP infusion, safety assessments will be performed before and after the infusion. 
At these visits, AEs as well as safety laboratory tests, ECG, weight, and vital signs, including body 
temperature, will be collected. Electronic patient-reported outcomes (ePROs) must be completed prior to 
infusion.
An interim futility analysis that is unblinded to a study independent team, evaluating efficacy, will be 
performed based on 204 randomized and treated patients who have had the chance of completing the Visit 6 
(Week 4). Randomized patients with an infusion on the same date, but after 204 patients have been treated, 
will also be included in the cut-off. Recruitment continues while the interim analysis is conducted. Based on 
the interim analysis result of the primary endpoint, a decision will be made to either continue the recruitment, 
or to end enrolment (see Interim Analysis below). Details of information flow and the interim process will be 
described in a separate interim analysis charter.
Blood samples for IMP quantification will be collected at regular intervals during the study (see Panel 2) and 
will be reported separately. 
The study design is presented in Panel 1 (including the study periods) and the scheduled study procedures and 
assessments are summarized in Panel 2.
Number of Patients Planned
304 patients recruited from specialist settings are planned for randomization: 152 patients in the eptinezumab 
400 mg group and 152 patients in the placebo group.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 7 of 112
Target Patient Population
Main Inclusion Criteria
The patient has episodic cluster headache, as defined by IHS ICHD-3 classification, with an adequately 
documented record or reliable history of eCH of at least 12 months prior to Screening Visit 1.
The patient has a prior history of cluster period(s) lasting 6 weeks or longer, when untreated.
The patient is able to distinguish cluster headache attacks from other headaches (i.e. tension-type headaches, 
migraine). 
The patient is, at Screening Visit 2, in cluster headache bout, characterized by the presence of at least one 
typical cluster headache attack, that started not later than 1 week prior to Screening Visit 2. In the opinion of the 
investigator the cluster headache bout is likely to continue for at least another 6 weeks based on prior cluster 
period history. Under exceptional circumstances, when a patient is able to attend Screening Visit 2 only during 
the second week after the first typical cluster headache attack, the possibility to enroll this patient in the study 
will be discussed with the investigator and the decision will be taken in the context of known history of typical 
duration of the bout for the individual patient. 
The patient has during Screening Period 2 based on prospectively collected information in the eDiary a weekly 
cluster headache attack frequency of a (this requirement should not be shared with the patient):
a. minimum of at least 7 total cluster headache attacks out of the 7-day Screening Period 2
b. maximum of 56 cluster headache attacks out of the 7-day Screening Period 2
The patient has an adequately documented record or reliable history of previous acute and preventive 
medication use for eCH, for at least 12 months prior to Screening Visit 1.
The patient has demonstrated compliance with the eDiary by entry of data for at least 6 of the 7 days of 
Screening Period 2. 
The patient has a medical history of first symptoms of cluster headache from <60 years of age.
The patient is aged ≥18 and ≤75 years at Screening Visit 1.
Main Exclusion Criteria
The patient has experienced failure on a previous treatment targeting the calcitonin gene-related peptide 
(CGRP) pathway (anti-CGRP mAbs and gepants). 
The patient has confounding and clinically significant pain syndromes (for example, fibromyalgia, complex 
regional pain syndrome).
The patient has a history or diagnosis of hypnic headache, hemicrania continua, new daily persistent headache, 
chronic migraine or unusual migraine subtypes such as hemiplegic migraine (sporadic and familial), recurrent 
painful ophthalmoplegic neuropathy, migraine with brainstem aura and migraine with neurological 
accompaniments that are not typical of migraine aura (diplopia, altered consciousness, or long duration).
Patients with a lifetime history of psychosis, bipolar mania, or dementia are excluded. Patients with other
psychiatric conditions whose symptoms are not controlled or who have not been adequately treated for a 
minimum of 6 months prior to Screening Visit 2 are also excluded. 
The patient is, at Screening Visit 2, at significant risk of suicide (either in the opinion of the investigator or 
defined, using the C-SSRS, as the patient answering: "yes" to suicidal ideation questions 4 or 5 or answering: 
"yes" to suicidal behaviour within the past month). Patients who do not meet this criterion, but who are 
considered by the investigator to be at significant risk for suicide, are excluded.
The patient has a history of clinically significant cardiovascular disease, including uncontrolled hypertension, 
ischaemia or thromboembolic events (for example, cerebrovascular accident, deep vein thrombosis, or 
pulmonary embolism).
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 8 of 112
The following recent and concomitant medications are disallowed or allowed with restrictions with respect to 
their use prior to or during the study (the list is not comprehensive):
a. Anti-CGRP therapies are disallowed for ≤5 half-lives for mAbs and ≤ 1 month for gepants prior to 
Screening Visit 2
b.Disallowed for 4 months prior to Screening Period 2 until the Safety Follow-Up Visit: botulinum toxin 
type A or B, that is administered in the head or neck area for treatment of cluster headache or other 
disorders, or for cosmetic use.
c. Disallowed for 2 months prior to Screening Period 1 until the Safety Follow-Up Visit: Psilocybin 
(mushrooms), LSD, or 2-bromo-LSD, or other illegal drugs 
d.Disallowed for 30 days prior to Screening Period 2 and until the end of Week 4: Greater occipital nerve 
(GON) block, injected and oral corticosteroids
e. Disallowed for 30 days prior to Screening Period 2 until the Safety Follow-Up Visit: 
i.
indomethacin 
ii.
any other cranial or extracranial nerve block; 
iii.
any neuromodulation treatment.
iv.
Gamma knife or other invasive procedures
f. Disallowed for 14 days prior to Screening Period 2 until the Safety Follow-Up Visit: methergine 
g.Stable dose (with restrictions on the maximum dose) for one month prior to Screening visit 2 and until 
the end of Week 4: verapamil, topiramate, gabapentin, valproate, candesartan and lithium. Melatonin is 
allowed at any time with a maximum dose 9mg/day
h.Abortive therapies for cluster headache attack allowed: high-flow oxygen; oral triptans, sumatriptan 
subcutaneous injection; sumatriptan nasal spray; zolmitriptan nasal spray; acetaminophen, NSAIDs, 
dihydroergotamine or ergot derivatives, octreotide
i. Allowed with restrictions: opioids, cannabinoids. 
Investigational Medicinal Product, Dose and Mode of Administration
Eptinezumab – 400 mg, Concentrate for Solution for Infusion 100 mg/ml added to 100 mL of 0.9% normal 
saline, intravenously
Placebo – 100 mL of 0.9% normal saline, intravenously
The IMP will be administered at Day 0 and at the end of Week 4, by intravenous infusion over 45 minutes 
(+15 minutes)
Assessment Details/Biomarker Methodology
Pharmacodynamic/Exploratory Biomarker Assessments
Blood sampling for exploratory plasma biomarker analyses (to be reported separately).
The assessments are summarized in Panel 2. Details for selected assessments are provided below.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 9 of 112
Assessment Details
The assessments are summarized in Panel 2. Details for selected assessments which are non-standard/require 
more explanation/description are provided below. All scales used to assess efficacy and pharmacoeconomic 
information in this study, are patient-reported instruments.
eDiary
Patients will complete a daily cluster headache eDiary from Screening Visit 2 until the Completion Visit (End 
of Week 16)/Withdrawal Visit consisting of applications and reports which will be used to derive the cluster 
headache endpoints and medication use. The eDiary will be distributed to each patient at Screening Visit 2 after 
patient training on eDiary use by site staff. The eDiary data from the 7-day Screening Period 2 will be used to 
determine eligibility criteria, baseline cluster headache characteristics and eDiary compliance. Ongoing 
evaluation of eDiary compliance will be performed by the study site based on eDiary reports. 
Sleep Impact Scale (SIS)
The SIS is a patient-reported scale to assess quality of life resulting from sleep disturbance. The SIS domains 
cover sleep impact on daily activities, emotional well-being, emotional impact, energy/fatigue, social well-
being, mental fatigue, and satisfaction with sleep. Each item is rated on a scale ranging from 1 (always) to 5 
(never). A higher score indicates better quality of life. It takes approximately 10 minutes to complete the 
questionnaire.
Health Care Resource Utilization (HCRU)
Cluster headache-specific healthcare resource utilization information will be collected in terms of outpatient 
health care professional visits, emergency room visits, hospital admissions, as well as duration of hospital stays. 
Clinical site personnel and patients will be instructed to capture utilization that takes place outside of visits 
associated with their participation in the clinical study.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 10 of 112
Statistical Methodology
The following analysis sets will be used to analyse and present the data:
all-patients-randomized set (APRS) - all randomized patients
all-patients-treated set (APTS) - all patients in the APRS who received infusion with double-blind IMP
all-patients-treated at interim set (APTS_IN) – all patients in the APRS who were among the first 204 that 
received infusion with double-blind IMP. Patients in the APTS that were infused on the same date, but after 
the first 204 will also be included.   
The efficacy analysis for the interim analysis will be based on the APTS_IN, and the final efficacy analysis will 
be based on the APRS. Demographics, baseline characteristics and safety tables will be based on the APTS.  
Baseline number of weekly attacks is derived from eDiary data collected in the Screening period 2 (day -7 to 
Day -1).
Unless otherwise specified, all testing will be done two-sided, based on a 5% significance level.
Primary analysis of the primary endpoint:
The primary endpoint, that will address the clinical question of interest, will be the change from Baseline in 
the number of weekly attacks (Weeks 1-2). The endpoint is based on eDiary data on attacks and the average 
number of weekly attacks across Week 1 and Week 2 will be estimated as presented below.
The strategy for imputation of missing data is given below and in details in the SAP:
Weekly scores are calculated using pro-rating, when data has been observed for at least 4 out of 7 days, with 
the weekly score = the average daily score x 7.
The primary analysis will use a placebo-based multiple imputation (pMI) method. Specifically, an analysis 
will be performed using a pattern-mixture model (PMM), in which after application of the prorating rule to 
data, any missing weekly scores will be imputed using a sequential regression-based multiple imputation 
method, based on the imputation models established from the placebo group.
The pMI will generate 200 simulated data sets with complete assessment of number of weekly attacks for 
Weeks 1, 2, 3, and 4. Each of these 200 data sets will be analysed using the following MMRM model:
The MMRM model based on data from all 4 weeks in the PBO-controlled period will include the following 
fixed effects: week (1, 2, 3, 4), country, and treatment as factors, baseline score as a continuous covariate, 
treatment-by-week interaction, and baseline score-by-week interaction. An unstructured variance structure 
will be used to model the within-patient errors. The Kenward-Roger approximation will be used to estimate 
denominator degrees of freedom. The mean difference between eptinezumab and placebo in the Change from 
Baseline in the number of weekly attacks (Weeks 1-2) will be estimated based on least square means for the 
treatment-by-week-interaction, using weights (1/2 1/2 0 0) for the eptinezumab by week estimates, and 
weights (-1/2 -1/2 0 0) for the placebo by week estimates.
The 200 results will be weighted together using Rubin’s rule to obtain a pMI estimate, confidence interval, 
and p-value.
Details are provided in the SAP. 
Analysis of the key secondary endpoints:
The continuous key secondary endpoints (change from Baseline in the number of weekly times an abortive 
medication was used (Weeks 1-2), and change from Baseline in the number of weekly days with <3 attacks 
per day (Weeks 1-2)) will be analysed using the MMRM model presented in the section on primary analysis 
using the baseline value of the variable as baseline. 
The change from Baseline in the number of daily attacks (Days 1-3) will be analysed using analysis of 
covariance (ANCOVA) including treatment and country as factors and baseline number of weekly attacks as 
covariate.  
The number of attacks starting <=24 hours after the start of the first infusion of IMP will be analysed using 
ANCOVA with treatment and country as factors and with the baseline number of weekly attacks as covariate.
The patients with 50% reduction from Baseline in the number of weekly attacks (Weeks 1-2) endpoint will 
be analysed using logistic regression where region and treatment are included as fixed factors and baseline 
number of weekly attacks is included as covariate.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 11 of 112
Time from first infusion of IMP to resolution of cluster headache bout within 4 weeks will be analysed using 
a Cox regression model with baseline number of weekly attacks as covariate and treatment and duration of 
current CH bout until infusion (1 or 2 weeks of screening period 2) as fixed factors.
Sensitivity analyses of the primary endpoint:
The impact of missing data in the derivation of the number of weekly attacks averaged across Weeks 1-2 and 
the impact of the use of transitional treatment will be evaluated by applying different methods of imputation. 
Details will be described in the SAP. 
Interim analysis:
An interim futility analysis will be performed based on 204 randomized and treated patients who have had the 
chance of completing the Week 4/Visit 6, to allow for stopping the study for futility if the level of efficacy is 
considerably lower than expected.  If the estimated treatment effect for the primary endpoint is less than 1/3 
of the expected effect size (3.00/3 = 1). Lundbeck may decide to stop the study for futility. The interim 
analysis will be performed by an independent CRO.
The independent CRO will inform a predefined group of Lundbeck employees whether the criterion for the 
interim futility have been met or not. No further details of the interim analysis results will be provided.
Details of the interim process will be described in a separate Interim Analysis Charter
Details of the statistical analysis for the interim analysis will be described in an Interim Statistical Analysis 
Plan
Testing Strategy
Primary endpoint
Change from Baseline in the number of weekly attacks (Weeks 1-2)
Key secondary endpoints
Response: 50% reduction from Baseline in the number of weekly attacks (Weeks 1-2)
Change from Baseline in the number of weekly times an abortive medication was used (Weeks 1-2)
Change from Baseline in the number of daily attacks (Days 1-3)
Change from Baseline in the number of weekly days with < 3 attacks per day (Weeks 1-2)
Time from first infusion of IMP to resolution of cluster headache bout (within the first 4 weeks)
Number of attacks starting <=24 hours after the start of the first infusion of IMP
A two-sided significance level of 0.05 will be used for the formal testing strategy.
The testing strategy will be a sequence of tests, testing one endpoint at a time. Only if one step has shown a 
statistically significant effect will the formal testing continue with the next step, thus ensuring protection of the 
type 1 error. The steps are described below.
Step 1
Test the primary endpoint using a 5.0% significance level. If the primary endpoint shows an advantageous 
effect of eptinezumab compared to placebo, the effect seen for the primary endpoint is considered statistically 
significant, and the testing continues with the next step.
Step 2
Test the first key secondary endpoint using a 5.0% significance level. If the first key secondary endpoint shows 
an advantageous effect of eptinezumab compared to placebo, the effect seen for the first key secondary 
endpoint is considered statistically significant, and the testing continues with the next step for the second key 
secondary endpoint.
Step 3
The steps for testing the key secondary endpoints in the order stated in the beginning of this section continues 
until a p-value >= 0.05 is encountered or all 6 key secondary endpoints are found to be statistically significant.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 12 of 112
Sample Size Considerations
Goadsby (2019) describes a study in eCH, where the first 4 weeks have a design similar to this study. The 
difference between galcanezumab and placebo in change from baseline in weekly frequency of attacks at 
Week 1 is estimated at -1.5 attacks, and at Week 2 is estimated at -4.4 attacks. The average difference to 
placebo across Week 1 and Week 2 is estimated at -3.0. Based on the CI presented in the publication, the SD at 
Week 1 is estimated at 9.2 and the SD at Week 2 is estimated at 11.1. Assuming that the correlation between 
Week 1 and Week 2 is 0.56, the SD for the average of Week 1 and 2 will be SD = 9.0. 
Assuming a difference of eptinezumab to placebo of -3.0 attacks with an SD = 9.0, 144 patients per treatment 
will provide 80% power for seeing an effect using a two-sided 5.0% significance level. Since the estimated 
treatment difference may be slightly decreased due to the use of pMI, an additional 5% of patients have been 
added. This yields a total of 152 patient per treatment.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 13 of 112
Panel 1
Study Design
The study consists of Screening Period 1 (up to 52 weeks), Screening Period 2 (7 days), a Placebo-controlled 
Period (4 weeks), an Active Treatment Period (4 weeks), a Post-treatment Observational Period (8 weeks) and a 
Safety Follow-up Period (8 weeks). After randomisation, IMP (eptinezumab 400 mg or placebo) is administered 
by intravenous infusion at Baseline (Day 0/Visit 3) and primary outcome is collected at Week 2. At the end of 
Week 4, all patients will receive a second IMP infusion (placebo or eptinezumab 400 mg) in a blinded manner, 
so that patients previously exposed to eptinezumab will receive placebo and patients randomized to placebo will 
receive eptinezumab 400 mg. For all subjects, who complete the study, a Safety Follow-up Visit will be 
conducted 20 weeks after the last infusion of IMP, that is at Week 24. For subjects who withdraw from the study, 
the Safety Follow-up Visit will be conducted 20 weeks after their last IMP infusion. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 14 of 112
Panel 2
Study Procedures and Assessments
Visit/Period Name
Screening
Placebo-controlled 
Period
Post-
Treatment 
Observational 
Period 
Screening Period 
1
Screening Period 
2
Baseline Visit 
Primary Outcome 
Visit 
Active Treatment 
Period
Completion Visit
SFU Visitc
Withdrawal Visitd
Visit Number
1a, gg
2a
3a
4b
5b
6a
7b
8b
9a
10a
WDa
Day/
End of Week
-371
to
-7/
-53 to
-1
-7 to -
1
0/
0
7/
1
14/
2
28/
4
56/
8
84/
12
112/
16
168
/24
Visit Windowe (days relative to 
nominal visit)
/1
1
1
1
/5
/5
/5
/5
Screening and Baseline Procedures and Assessments
Signed informed consent(s)
f
g
Demographics (age, sex, race)

Diagnosis


Disease-specific historyh

Relevant history (social, 
medical, psychiatric, 
neurological)


Previous cluster headache 
abortive, transitional and 
preventive therapy useh


Recent medication (past 3 
months prior to the Screening 
Visit 1/ Screening Visit 2)


Substance Use (e.g. smoking, &
alcohol)


Height

Family history of cluster 
headache

Urine drug screen

Inclusion/exclusion criteriai



Current cluster headache 
symptoms









LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 15 of 112
Visit/Period Name
Screening
Placebo-controlled 
Period
Post-
Treatment 
Observational 
Period 
Screening Period 
1
Screening Period 
2
Baseline Visit 
Primary Outcome 
Visit 
Active Treatment 
Period
Completion Visit
SFU Visitc
Withdrawal Visitd
Visit Number
1a, gg
2a
3a
4b
5b
6a
7b
8b
9a
10a
WDa
Day/
End of Week
-371
to
-7/
-53 to
-1
-7 to -
1
0/
0
7/
1
14/
2
28/
4
56/
8
84/
12
112/
16
168
/24
Visit Windowe (days relative to 
nominal visit)
/1
1
1
1
/5
/5
/5
/5
Signs and symptoms present at
Screening Visit 2 and Baseline 
Visit (before IMP 
administration) - recorded on an 
Adverse Event Formhh


Randomization

Efficacy Assessments (ePROs) j,k
eDiary daily recordingl

m


m



eDiary compliance checkn








PGIC


m



SIS
m

m

Pharmacoeconomic Assessments (ePROs)
EQ-5D-5L
m

m



HCRU j
m
m
WPAI:GH2.0 j
m
m
Pharmacokinetic Assessments
Blood sampling for IMP 
quantification
o
o



Pharmacodynamic Assessments
Blood sampling for exploratory 
biomarkers
o
o



Safety Assessments
Adverse events
hh
p,q,r


p,q,r





Blood and urine sampling for 
clinical safety laboratory tests 

q
q



LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 16 of 112
Visit/Period Name
Screening
Placebo-controlled 
Period
Post-
Treatment 
Observational 
Period 
Screening Period 
1
Screening Period 
2
Baseline Visit 
Primary Outcome 
Visit 
Active Treatment 
Period
Completion Visit
SFU Visitc
Withdrawal Visitd
Visit Number
1a, gg
2a
3a
4b
5b
6a
7b
8b
9a
10a
WDa
Day/
End of Week
-371
to
-7/
-53 to
-1
-7 to -
1
0/
0
7/
1
14/
2
28/
4
56/
8
84/
12
112/
16
168
/24
Visit Windowe (days relative to 
nominal visit)
/1
1
1
1
/5
/5
/5
/5
Blood sampling for ADA
including NAbs
q



Vital signs (including body 
temperature), weight
s

q,r
q,r



ECG

q
q



Examinations (physical, 
neurological)t






C-SSRSu

q
q




Biobankingv
Blood sampling for gene 
expression profiling (RNA)w




Blood sampling for future 
exploratory biomarkersw
o
o

Blood sampling for 
metabolomics/proteomics
(plasma)w




Blood sampling for 
pharmacogenetics (DNA) 
(optional)x

Blood sampling for possible 
future ADA assessmentw,y
z



Other Study Procedures and Assessments
IMP administered (IV infusion)aa
bb
bb
IMP accountabilitycc


Concomitant medication 
(prescription and non-
prescription)

q


q





LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 17 of 112
Visit/Period Name
Screening
Placebo-controlled 
Period
Post-
Treatment 
Observational 
Period 
Screening Period 
1
Screening Period 
2
Baseline Visit 
Primary Outcome 
Visit 
Active Treatment 
Period
Completion Visit
SFU Visitc
Withdrawal Visitd
Visit Number
1a, gg
2a
3a
4b
5b
6a
7b
8b
9a
10a
WDa
Day/
End of Week
-371
to
-7/
-53 to
-1
-7 to -
1
0/
0
7/
1
14/
2
28/
4
56/
8
84/
12
112/
16
168
/24
Visit Windowe (days relative to 
nominal visit)
/1
1
1
1
/5
/5
/5
/5
eDiary training

ePRO training

eDiary closeoutdd


Pregnancy testee


q
q



ADA = anti-drug antibody; BL = baseline; C-SSRS = Columbia-Suicide Severity Rating Scale; EQ-5D-5L=
EuroQol 5-Dimension 5-Level; HCRU = Health Care Resources Utilization; IMP = investigational medicinal 
product; IV = intravenous; PGIC = Patient Global Impression of Change; ePRO = electronic patient-reported 
outcome; SAE = serious adverse event; SFU = Safety Follow-up; SIS = Sleep Impact Scale; WD = Withdrawal; 
WPAI:GH2.0 = Work Productivity Activity Questionnaire: General Health second version
a
This visit should be a site visit. The Screening Visit 1 assessments may be extended over several days if 
needed. The date of the first assessment (except ICF) should be entered in the IRT system as the Visit Date.
b
For phone visits, the patient will be contacted for eDiary compliance check, to ensure that the selected 
assessments have been completed and for collection of relevant information such as AEs and concomitant 
medications.
c
The Safety Follow-Up Visit (SFU), should be scheduled 20 weeks (5 half-lives) after the last IMP 
administration.
d
Patients who withdraw, except for those who withdraw their consent, will be asked to attend a Withdrawal 
Visit as soon as possible.
e
If the date of a clinic visit or phone contact does not conform to the schedule, subsequent visits should be 
planned to maintain the visit schedule relative to the Baseline Visit (Day 0/Visit 3).
f
At Screening Visit 1, the patient will be asked to sign the main Informed Consent Form and the Informed 
Consent Form for blood sampling for pharmacogenetics (optional). Under exceptional circumstances, such as 
where COVID-19 pandemic restrictions impact the ability to perform site visits, the discussion with the 
patients about the Informed Consent Form(s) can be done as a virtual clinic visit and the Informed Consent 
Form(s) can be provided remotely. Refer to section 4.2.
g
At Screening Visit 2, the patient will be asked to confirm consent by re-signing each of the Informed Consent 
Form(s) signed at Screening Visit 1 (separate signature lines on each form).
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 18 of 112
h
Patients must have adequately documented records or reliable history of episodic cluster headache history 
and previous treatment for episodic cluster headache within the 12 months prior to Screening Visit 1. See 
protocol for definition of adequately documented records.
i
Patients who meet inclusion criteria 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 15, 18 and none of exclusion criteria 1, 2, 4, 
5, 6, 7, 8, 9 (At Screening Visit 1, the investigator must consider excluding patients with a lifetime history of 
psychosis, bipolar mania, or dementia. Patients with other psychiatric conditions, whose symptoms at 
Screening Visit 1, are not controlled or who have not been adequately treated must be identified and the 
investigator should consider initiation of appropriate treatment as medically indicated), 10, 11, 12, 13, 14 
(Patients with uncontrolled hypertension at Screening Visit 1, must be identified and the investigator must 
consider initiation of appropriate treatment as medically indicated), 15, 16, 17, 20, 24, 25, 26, 27, 28, 29 at 
Screening Visit 1 are eligible to enter Screening Period 1. Patients who meet all of the inclusion and none of 
the exclusion criteria at the Screening Visit 2 and Baseline Visit (Day 0/Visit 3) are eligible to participate in 
this study.
j
During the Placebo-controlled Period, ePROs which are scheduled in alignment with a clinic visit must be 
completed in the clinic; ePROs which are scheduled in alignment with a phone contact must be completed in 
the remote setting on the day of the scheduled phone contact date. During the Active Treatment Period and 
Post-treatment Observational Period, ePROs which are scheduled in alignment with a clinic visit can be 
completed in the clinic or in the remote setting within 1 day prior to the scheduled clinic visit date. ePROs 
which are scheduled in alignment with a phone contact must be completed in the remote setting and can be 
completed on the day or within 1 day prior to the scheduled phone contact date. HCRU and WPAI:GH2.0 
must be administered at site.
k
At the Screening Visit 2, the patient must be assisted with the provisioning and training of the eDiary and 
ePROs. Details will be provided in a separate training module.
l
Patients must complete the eDiary from the first day of Screening Period 2 until the Completion Visit 
(Week 16/Visit 9).
m Patients must complete the daily eDiary and ePRO entries prior to infusion.
n
In addition to the eDiary compliance checks performed at the defined clinic visits and phone contacts, 
ongoing evaluation of eDiary compliance will be performed by the site (based on eDiary reporting) and more 
frequent contact with patients may be performed in case of non-compliance.
o
At IMP visits, two blood samples will be collected for IMP quantification and exploratory biomarkers – one 
prior to the IMP infusion and one - one hour after the end of the infusion.
p
Infusion Related Reactions must be checked as part of the overall AE collection, after infusion and before the 
patient is discharged from the site.
q
Infusion must be preceded by the assessment of vital signs including body temperature, concomitant 
medications, AEs, ECG, blood sampling (for clinical safety laboratory tests and ADA), urine sampling (for 
clinical safety laboratory and pregnancy tests) and C-SSRS. Vital signs must be assessed prior to blood 
sampling.
r
Vital signs including body temperature and AEs must be checked after infusion. Vital signs must be assessed 
prior to blood sampling.
s
At Screening Visit 1, only vital signs and weight are assessed. It is recommended to calculate BMI at 
Screening Visit 1 to assess Exclusion Criterion 9 in preparation for the eligibility assessment of BMI at 
Screening Visit 2. 
t
Physical and Neurological examinations for all clinic visits (except Screening Visit 2 which is mandatory)
are to be conducted at the discretion of the investigator. If these examinations are conducted at an IMP 
infusion Visit, these must be performed prior to the infusion.
u
C-SSRS will be administered by the authorized rater at the clinic.
v
Biobank may be excluded or optional per local regulation.
w Exploratory gene expression profiling (RNA) and metabolomics/proteomics, including blood sampling for 
possible future ADA assessment and future exploratory biomarkers, is covered by the main Informed 
Consent Form.
x
Sampling for pharmacogenetics is optional and covered by a separate Informed Consent.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 19 of 112
y
Blood samples for serum separation and possible future ADA analyses will be drawn at Baseline 
(Day 0/Visit 3), Completion (Week 16/Visit 9), Safety Follow-Up Visit, or the Withdrawal Visit (if the 
patient withdraws).
z
Blood samples for ADA at Baseline (Day 0/Visit 3) will be collected prior to the IMP infusion.
aa An unblinded pharmacist or designee is responsible for receiving, storing and preparing IMP. The pharmacist 
or designee will not be responsible for other aspects of the clinical study where blinding is necessary.
bb Patients must be monitored during the infusion and for a period of 1 hour from the end-of-infusion. Patients 
will be requested to stay longer should the investigator or designee determine this is clinically warranted.
cc A designated unblinded CRA is responsible for the IMP accountability.
dd The eDiary closeout will take place at Completion (Week 16/Visit 9) / Withdrawal Visit (for patients who 
withdraw). Details will be provided in a separate training module.
ee For women of childbearing potential, pregnancy test at Screening Visit 2 and the Safety Follow-up Visit is to 
be conducted using serum β-HCG. At all other visits, urine pregnancy testing will be performed and in case 
of a positive finding, further confirmatory testing will be performed via serum β-HCG.
gg For patients who enter the study already in cluster headache bout, Screening Visit 1 and Screening Visit 2 
may be combined to capture all assessments for Screening Visit 1 and Screening Visit 2 on the same day.
hh Adverse events (serious and non-serious) must be collected, recorded, and reported to Lundbeck from the 
time the patient has signed/re-signed the informed consent form(s) at Screening Visit 2.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 20 of 112
Table of Contents
List of Panels.................................................................................................................................25
List of Abbreviations and Definitions of Terms ........................................................................26
Major Changes Since Last Edition.............................................................................................28
1
Introduction .........................................................................................................................29
1.1
Background................................................................................................................29
1.1.1
Overview....................................................................................................29
1.1.2
Nonclinical Data.........................................................................................30
1.1.3
Clinical Data...............................................................................................31
1.2
Rationale for the Study ..............................................................................................32
2
Objectives and Endpoints ...................................................................................................33
3
Study Design.........................................................................................................................35
3.1
Overview of the Study Design...................................................................................35
3.2
Rationale for the Study Design..................................................................................38
3.3
Benefit-Risk Assessment...........................................................................................40
4
Ethics ....................................................................................................................................42
4.1
Ethical Rationale........................................................................................................42
4.2
Informed Consent ......................................................................................................45
4.3
Personal Data Protection............................................................................................47
4.4
Ethics Committees and Institutional Review Boards.................................................47
5
Study Population .................................................................................................................48
5.1
Number of Patients and Regions ...............................................................................48
5.2
Patient Recruitment ...................................................................................................48
5.3
Selection Criteria .......................................................................................................48
5.4
Withdrawal Criteria ...................................................................................................52
6
Investigational Medicinal Product (IMP)..........................................................................53
6.1
Treatment Regimen ...................................................................................................53
6.2
IMP, Formulation, and Strength ................................................................................54
6.3
Manufacturing, Packaging, Labelling, and Storage of IMP ......................................54
6.4
Method of Assigning Patients to Treatment ..............................................................55
6.5
IMP Accountability ...................................................................................................55
6.6
Unblinding Procedures ..............................................................................................55
7
Concomitant Medication.....................................................................................................56
7.1
Concomitant Medication ...........................................................................................56
8
Study Visit Plan ...................................................................................................................57
8.1
Overview ...................................................................................................................57
8.2
Screening Visit 1........................................................................................................59
8.3
Screening Visit 2........................................................................................................60
8.3.1
Pre-screening..............................................................................................60
8.3.2
Patient Identification Card..........................................................................60
8.3.3
Re-Screening Visit 1 ..................................................................................60
8.3.4
Re-screening Visit 2...................................................................................61
8.3.5
Extension of Screening Period 2 ................................................................62
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 21 of 112
8.4
Baseline Visit + IMP (Day 0/Visit 3) ........................................................................63
8.5
Visit 6 + IMP .............................................................................................................63
8.6
IMP Visits (Visits 3 and 6) ........................................................................................64
8.7
Phone Contacts (Visits 4, 5, 7, 8) ..............................................................................65
8.8
Completion Visit (Visit 9) .........................................................................................65
8.9
Withdrawal Visit........................................................................................................65
8.10
Safety Follow-up Visit (Visit 10) ..............................................................................66
8.11
Unscheduled Visit......................................................................................................66
8.12
End-of-study Definition.............................................................................................67
9
Assessments..........................................................................................................................67
9.1
Screening and Baseline Procedures and Assessments...............................................67
9.1.1
Demographics and Baseline Characteristics ..............................................67
9.1.2
Diagnostic Assessments .............................................................................68
9.1.3
Drug and Alcohol Screen ...........................................................................69
9.2
Efficacy Assessments ................................................................................................69
9.2.1
Clinical Outcome Assessments (COAs).....................................................69
9.2.1.1
Use of COA Tools .....................................................................69
9.2.1.2
eDiary.........................................................................................70
9.2.1.3
Patient Global Impression of Change (PGIC)............................71
9.2.1.4
Sleep Impact Scale (SIS) ...........................................................71
9.2.1.5
External COA Monitoring Oversight.........................................71
9.2.1.6
COA Tool Training....................................................................72
9.3
Pharmacoeconomic Assessments ..............................................................................72
9.3.1
Clinical Outcome Assessments (COAs).....................................................73
9.3.1.1
Use of COA Tools .....................................................................73
9.3.1.2
Euroqol 5 Dimension – 5 Levels (EQ-5D-5L)...........................73
9.3.1.3
Health Care Resource Utilization (HCRU)................................73
9.3.1.4
Work Productivity and Activity Impairment: General Health 
version 2 (WPAI:GH2.0)...........................................................73
9.3.1.5
External COA Monitoring Oversight.........................................73
9.3.1.6
COA Training ............................................................................74
9.4
Pharmacokinetic Assessments...................................................................................74
9.4.1
Blood sampling for eptinezumab quantification ........................................74
9.5
Pharmacodynamic Assessments ................................................................................74
9.5.1
Pharmacodynamic/Exploratory Biomarkers ..............................................74
9.6
Safety Assessments....................................................................................................74
9.6.1
Adverse Events...........................................................................................74
9.6.2
Clinical Safety Laboratory Tests................................................................74
9.6.3
Vital Signs..................................................................................................76
9.6.4
Height and Weight .....................................................................................76
9.6.5
Electrocardiograms (ECGs) .......................................................................77
9.6.6
Physical and Neurological Examinations...................................................77
9.6.7
Columbia-Suicide Severity Rating Scale ...................................................77
9.6.8
Anti-Drug Antibody (ADA) including Neutralizing Antibody (Nab) 
Assessments ...............................................................................................78
9.7
Biobanking.................................................................................................................78
9.7.1
General Considerations ..............................................................................78
9.7.2
Blood Sampling for Gene Expression Profiling.........................................79
9.7.3
Blood Sampling for Metabolomics and/or Proteomics ..............................79
9.7.4
Blood Sampling for Pharmacogenetics ......................................................80
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 22 of 112
9.7.5
Blood sampling for possible future anti-drug antibody assessments .........80
9.7.6
Blood Sampling for Future Exploratory Biomarkers .................................80
9.8
Order of Assessments ................................................................................................81
9.9
Total Volume of Blood Drawn and Destruction of Biological Material ...................82
9.10
Treatment Compliance...............................................................................................82
10
Adverse Events.....................................................................................................................82
10.1
Definitions .................................................................................................................82
10.1.1
Adverse Event Definitions .........................................................................82
10.1.2
Adverse Event Assessment Definitions .....................................................84
10.1.3
Management of Reactions to Study Drug ..................................................85
10.2
Pregnancy ..................................................................................................................85
10.3
Recording Adverse Events ........................................................................................85
10.4
Reporting Serious Adverse Events (SAEs) ...............................................................86
10.5
Treatment and Follow-up of Adverse Events............................................................87
11
Data Handling and Record Keeping..................................................................................87
11.1
Data Collection..........................................................................................................87
11.1.1
Electronic Case Report Forms (eCRFs) .....................................................87
11.1.2
Patient Binders ...........................................................................................88
11.1.2.1
Use of Patient Binders ...............................................................88
11.1.2.2
Serious Adverse Event Fallback Forms.....................................88
11.1.3
External Data..............................................................................................88
11.2
Retention of Study Documents at the Site.................................................................88
11.2.1
eCRF Data..................................................................................................88
11.2.2
Other Study Documents .............................................................................89
12
Monitoring Procedures .......................................................................................................90
13
Audits and Inspections........................................................................................................91
14
Protocol Compliance ...........................................................................................................91
15
Study Termination...............................................................................................................91
16
Statistical Methodology.......................................................................................................93
16.1
Responsibilities..........................................................................................................93
16.2
Analysis Sets..............................................................................................................93
16.3
Descriptive Statistics .................................................................................................94
16.4
Patient Disposition.....................................................................................................94
16.5
Demographics and Baseline Characteristics..............................................................94
16.6
Recent and Concomitant Medication.........................................................................94
16.7
Exposure ....................................................................................................................94
16.8
Efficacy Analyses ......................................................................................................95
16.8.1
General Efficacy Analysis Methodology ...................................................95
16.8.1.1
Primary Estimand ......................................................................95
16.8.2
Strategies for Addressing Intercurrent Events in Primary Estimand..........96
16.8.3
Primary Analysis of the Primary Endpoint ................................................97
16.8.4
Details are provided in the SAP.Sensitivity Analyses of the Primary 
Endpoint .....................................................................................................98
16.8.5
Analysis of the Key Secondary Endpoints.................................................98
16.8.6
Testing Strategy..........................................................................................99
16.8.7
Analysis of the Secondary Endpoints.........................................................99
16.8.8
Analysis of the Exploratory Endpoints ....................................................100
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 23 of 112
16.8.9
Analysis of Subgroups .............................................................................101
16.9
Safety Analyses .......................................................................................................101
16.9.1
Analysis of Adverse Events .....................................................................101
16.9.2
Analysis of Other Safety Endpoints .........................................................101
16.10 Interim Analyses......................................................................................................101
16.11 Sample Size and Power ...........................................................................................102
16.12 Statistical Analysis Plan ..........................................................................................102
17
Clinical Study Report and Publications ..........................................................................102
17.1
Data Ownership .......................................................................................................102
17.2
Clinical Study Report ..............................................................................................102
17.3
Summary of Clinical Study Results.........................................................................103
17.4
Publications..............................................................................................................103
18
Indemnity and Insurance..................................................................................................103
19
Finance................................................................................................................................103
19.1
Site Agreements.......................................................................................................103
19.2
Financial Disclosure ................................................................................................103
19.3
Equipment................................................................................................................103
References ...................................................................................................................................104
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 24 of 112
Appendices
Appendix I
Clinical Study Protocol Authentication and Authorization..............................108
Appendix II
Recent and Concomitant Medication Disallowed or Allowed with Restrictions
..........................................................................................................................110
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 25 of 112
List of Panels
Panel 1
Study Design............................................................................................................. 13
Panel 2
Study Procedures and Assessments.......................................................................... 14
Panel 3
Objectives and Endpoints ......................................................................................... 33
Panel 4
Dosing Schedule....................................................................................................... 54
Panel 5
IHS ICHD-3 guidelinesfor Episodic Cluster Headache............................................ 68
Panel 6
Clinical Safety Laboratory Tests .............................................................................. 75
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 26 of 112
List of Abbreviations and Definitions of Terms
ADA
anti-drug antibody
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
APRS
all-patients-randomized set
APTS
all-patients-treated set
AST
aspartate aminotransferase
β-hCG
beta-human chorionic gonadotropin
BMI
body mass index
BSC
best supportive care
CGRP
calcitonin gene-related peptide
CH
Cluster Headache
CI
confidence interval
Cmax
maximum observed concentration
COVID-19
coronavirus disease 2019
CRA
clinical research associate
CRO
clinical research organization
CSR
clinical study report
DNA
deoxyribonucleic acid
DSM-5®
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
EC
ethics committee
ECG
electrocardiogram
eCH
episodic Cluster Headache
eCRF
electronic case report form
ePRO
electronic patient-reported outcome
EQ-5D-5L
Euroqol 5 Dimensions
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FAS
full-analysis set
FDA
Food and Drug Administration
GON
greater occipital nerve
hCG
human chorionic gonadotropin
HCRU
health care resource utilization
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
IMP
investigational medicinal product
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 27 of 112
IND
Investigational New Drug Application
IRB
institutional review board
IRR
infusion-related reaction
IRT
interactive response technology
IV
intravenous
Lu
Lundbeck
mAbs
monoclonal antibodies
NAb
neutralizing antibody
NOAEL
no-observed-adverse-effect level
PCR
polymerase chain reaction
PK
pharmacokinetic(s)
PR
specific ECG interval describing atrioventricular conduction 
QP
qualified person
QRS
specific ECG interval describing ventricular depolarization
QT
specific ECG interval describing ventricular depolarization/repolarization
QTc
heart-rate corrected QT interval
QTcF
heart-rate corrected QT interval using Fridericia’s correction formula
RR
specific ECG interval describing the ventricular depolarization/repolarization cycle
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SFU
Safety Follow-Up
SNP
single-nucleotide polymorphism
SUSAR
suspected unexpected serious adverse reaction
t½
apparent elimination half-life
TEAE
treatment-emergent adverse event
TMF
trial master file
WPAI:GH2.0
Work Productivity and Activity Impairment, General Health second version
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 28 of 112
Major Changes Since Last Edition
No major changes have been made since the last edition of this CSP.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 29 of 112
1
Introduction
1.1
Background
1.1.1
Overview
Episodic cluster headache is a rare but disabling primary headache disorder characterized by 
episodic attacks of intense unilateral headache, frequently associated with autonomic 
symptoms such as lacrimation, conjunctival injection, and nasal congestion (IHS ICHD-3).1
The diagnosis of cluster headache (CH) is distinctly recognized and defined by the ICHD-3. 
The natural course of illness of episodic cluster headache can be conceptualized as consisting 
of two phases: (1) cluster periods (typically lasting weeks or months) composed of a series of 
15-180 minute attacks of severe (often excruciating) unilateral headache pain attacks and 
cranial autonomic symptoms occurring near-daily to multiple times daily during the cluster 
period, and (2) attack-free remission periods that may last for weeks, months, or even years. 
The social impact of cluster headache is considerable2 and it is associated with substantial 
direct and indirect economic consequences.3 Cluster headache has a prevalence of 0.1% with 
a 2-6 times higher average incidence rate for males compared to females.4 However, the ratio 
might be lower due to misdiagnosis of cluster headache in females compared to males.5 The 
life-time prevalence of cluster headache, based on a meta-analysis, showed a mean prevalence 
of 124 per 100,000, where episodic form was six times more prevalent than the chronic form
that unlike the episodic form has no remission period, or the remissions lasts <3 months.1,4
There are significant unmet needs for just about every clinical aspect of the patient with 
cluster headache, particularly related to the severity of the disease and treatment options. Most 
patients experiencing cluster headache attacks rate their pain intensity as near to or at the 
worst pain imaginable (using a Visual Analog Scale).6
The currently available preventive pharmacological treatments are unspecific, insufficient, 
and hampered by side-effects. First line of acute treatment is sumatriptan administered 
subcutaneously7,8,9 and inhalation of 100% oxygen.10,11,12,13 Preventive therapies are 
subdivided into maintenance and transitional treatments. Transitional treatment is often used 
to relieve the patient until maintenance prophylactic is adequately titrated and consists of oral 
steroids or greater occipital nerve (GON) blocks.14,15 Maintenance treatment aims to reduce 
attack frequency with verapamil being first-choice, but only 50-80% of CH patients are 
responders;16 and its use is hampered by side-effects since many patients need high doses. 
Other preventive treatments are less attractive due to their side-effect profile, the scarcity of 
evidence17,18 and high cost.19 In the clinic, several types of treatment are combined in the 
effort to provide relief to the patients and increase the quality of life. 
Increased plasma or serum levels of calcitonin gene-related peptide (CGRP) have been 
associated with painful syndromes such as migraine and cluster headache.20 Cluster headache 
patients have higher CGRP-levels compared to migraine patients and healthy controls.21 As in 
migraine,22 CGRP levels are altered during attacks. Recently, a provocation study supported 
the central role of CGRP involvement in CH as infusion of CGRP induced attacks in 89% of 
episodic CH patients in an active bout.23
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 30 of 112
Eptinezumab is a humanized monoclonal antibody that inhibits the action of calcitonin gene-
related peptide (CGRP) and is approved by the Food and Drug Agency (FDA) as the first and 
only intravenous preventive treatment for migraine. Eptinezumab is administered by IV 
infusion every 12 weeks offering a route of drug administration with 100% bioavailability 
that allows for rapid CGRP inhibition. Eptinezumab IV infusion administered every 12 weeks 
by a healthcare professional helps to ensure treatment adherence and delivery of a known 
quantity of drug with each dose. In clinical studies, treatment with eptinezumab has been 
associated with a robust and clinically meaningful migraine reduction as early as the day after 
the first infusion, a sustained efficacy throughout the treatment period and an acceptable 
tolerability profile with low incidences of study drug withdrawal due to adverse events.
The following sections 1.1.2 and 1.1.3 provide a brief overview of the nonclinical and clinical 
data currently available for eptinezumab. Refer to the current version of the Investigator’s 
Brochure24 for more detailed information.
1.1.2
Nonclinical Data
Data from the comprehensive program of nonclinical studies support the clinical mechanism 
of action and safety of eptinezumab.
To demonstrate the ability of eptinezumab to block CGRP-driven vasodilation in vivo, several 
primary pharmacodynamic animal studies were conducted in rat, cynomolgus monkey and 
rabbit. The administration of eptinezumab was well tolerated at doses up to 100 mg/kg, the 
highest dose administered, and inhibited increases in dermal blood perfusion induced by 
either topical capsaicin (rats and monkey) or intradermal β-CGRP challenge (rabbit). The 
pharmacodynamic effects were dose-dependent and occurred from 0.1 mg/kg. The 
appropriateness of the nonclinical species has been established in vitro (rat and rabbit). Across 
species (including human), eptinezumab has a binding affinity in the low picomolar range for 
α-and β-CGRP and has been shown to functionally inhibit α-and β-CGRP with high 
specificity. 
Intravenous administration of eptinezumab, either as a single- or multiple-dose for 1-month 
duration up to 100 mg/kg/dose in rats or monkeys, or multiple-dose for 6-months duration up 
to 150 mg/kg/dose in monkeys, was well tolerated. No mortality or adverse findings attributed 
to the pharmacological activity of eptinezumab were observed in the single- or repeat-dose 
studies in rats or cynomolgus monkeys. As determined during a 6-month chronic toxicity in 
cynomolgus monkeys, the NOAEL of 150 mg/kg/dose supports a 103-fold or 123-fold safety 
margin by Cmax or AUC for the highest dose, 300 mg, of eptinezumab administered by 
IV infusion every 12 weeks in humans. 
Overall, following IV administration in the nonclinical studies, eptinezumab exposure was 
generally dose proportional, and the plasma-concentration profiles were consistent for IV 
administration with the rapid achievement of Cmax followed by a mono-exponential decline.
The volume of distribution (Vc) for eptinezumab is generally limited to the vascular 
compartment.24
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 31 of 112
Eptinezumab is unlikely to interact directly with DNA or other chromosomal material, and 
under ICH S6(R1) guidance, evaluations for potential genotoxicity were considered 
unnecessary and were not performed for eptinezumab. Based on extensive evaluation of the 
literature related to inhibition of CGRP, angiogenesis, and tumor growth as well as the 
absence of eptinezumab-related proliferative findings from long-term studies in monkeys, no 
further nonclinical studies addressing the carcinogenic risk are considered necessary. 
In conformance with applicable guidance documents, a complete package of 
reproductive/development toxicity studies were conducted. In these studies, administration of 
eptinezumab by intravenous injection to pregnant female rats or rabbits at 75 or 
150 mg/kg/dose was well tolerated. No effects on male or female reproductive function or 
performance, fertility or early embryonic development in rats were observed. No parental 
effects or evidence of embryo-lethality, fetotoxicity, or teratogenicity in rats or rabbits were 
observed. There were no effects on the survival, physical development, behavior or 
reproductive performance of the F1 generation in the pre- and postnatal development study in 
rats.
The local tolerance of eptinezumab was assessed following multiple dose studies in rats and 
cynomolgus monkeys utilizing eptinezumab administered IV. No gross observations 
including erythema and edema, or toxicologically significant histological changes at the 
injection site(s) were noted in either species for any dose route at concentrations up to 
100 mg/mL eptinezumab. 
Biologics in general have minimal risks regarding drug-drug interactions;25 therefore, drug 
interactions with eptinezumab and concomitant medications are not expected, and nonclinical 
studies evaluating the potential for interactions with drugs that may be co-administered with 
eptinezumab were not performed.
1.1.3
Clinical Data
The clinical program of eptinezumab is composed of 5 completed studies to date; 4 studies are 
placebo-controlled (Phase Ib study in frequent episodic migraine (ALD403-CLIN-002),26
Phase II study in chronic migraine (ALD403-CLIN-005),27 PIII study in frequent episodic 
migraine (ALD403-CLIN-006),28 PIII study in chronic migraine (ALD403-CLIN-011)29 and 
1 study is open-label (PIII study in chronic migraine (ALD403-CLIN013)).30,31 Phase III 
study (18903A)32 is ongoing to assess treatment of eptinezumab in patients experiencing an 
acute attack of migraine. A further Phase I study is initiated to assess the safety and PK in 
Japanese healthy volunteers (18899A).
Eptinezumab is administered by 30-45 minute IV infusion, which bypasses extravascular 
absorption routes and renders 100% bioavailability. The time required to achieve therapeutic 
concentrations for eptinezumab is rapid and maximum observed plasma concentration (Cmax) 
is typically observed at the end of infusion. The low plasma clearance (0.15 L/d) and 
protracted terminal-elimination half-life (t½) of 27 days for eptinezumab support a sustained 
duration of effect and infrequent, once every 12 weeks dosing in migraine preventive 
treatment. The mean accumulation ratios based on Cmax and AUC0-tau are 1.08 and 1.15, 
respectively. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 32 of 112
Eptinezumab is not metabolized by cytochrome P450 enzymes. Therefore, interactions by 
eptinezumab with concomitant medications that are substrates, inducers, or inhibitors of 
cytochrome P450 enzymes are considered unlikely.33 Nevertheless, the co-administration of 
eptinezumab in combination with sumatriptan was investigated in Study ALD403-CLIN001.24
The co-administration of sumatriptan did not appear to alter the single dose PK of 
eptinezumab. Similarly, the PK of sumatriptan was not impacted upon by the 
co-administration of eptinezumab.
Results from the two pivotal, placebo-controlled, Phase III trials showed that eptinezumab at 
doses of 100 mg or 300 mg administered by IV infusion every 12 weeks (2 infusions) led to 
significant reductions in monthly migraine days in patients with episodic or chronic migraine 
(ALD403-CLIN-006 and ALD403-CLIN-011).28,29 Both eptinezumab 300 mg and 100 mg 
groups achieved the primary efficacy endpoint and all key secondary endpoints in the 
prespecified statistical hierarchy. The therapeutic benefit resulting from administration of 
eptinezumab for the preventive treatment of migraine in adults is robust and clinically 
meaningful, as demonstrated by the results of the 75% and 50% migraine responder analyses. 
Administration of eptinezumab 100 or 300 mg resulted in a rapid, migraine preventive effect 
that was established on the day after the first infusion and maintained over the 12-week 
dosing cycle. Both eptinezumab doses were associated with a consistent pattern of statistically 
significant and clinically meaningful efficacy across these endpoints compared with placebo. 
The safety of eptinezumab has been evaluated in more than 2,400 subjects in doses up to 
1000 mg. Long-term data with eptinezumab is limited; however, in study ALD403-CLIN-013 
a total of 100 patients have been treated with the 300 mg dose and completed the study at 
Week 104 and no new significant findings have been identified during the long-term follow 
up. In patients with migraine, nasopharyngitis and hypersensitivity reactions, including 
anaphylactic reactions, are considered adverse drug reactions for eptinezumab. In the pivotal 
Phase III studies (ALD403-CLIN-006 and ALD403-CLIN-011) hypersensitivity reactions 
were reported with multiple related adverse event terms, such as hypersensitivity, 
angioedema, urticaria, flushing/hot flush, rash and pruritus. These events were reported in 
approximately 4% of patients on 300 mg eptinezumab, 3% of patients on 100 mg 
eptinezumab and 1% of patients on placebo. Serious hypersensitivity reactions have been 
reported, including anaphylactic reactions on rare occasions. In most cases, the events 
developed during or within minutes of the infusion and subjects recovered following drug 
discontinuation and adequate treatment.
The safety findings to date indicate that eptinezumab is well tolerated and demonstrates a 
favorable risk-benefit profile based on review of nonclinical, clinical, and scientific literature 
data.
1.2
Rationale for the Study
Cluster headache is an excruciatingly painful primary headache disorder, which places an 
exceptional burden on those affected. Few, if any, medical disorders are more painful than 
cluster headache. Patients describe the pain of a single attack as being worse than anything 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 33 of 112
else they have experienced. The severity of the pain has earned it the sobriquet “suicide 
headache,” although this is a rare occurrence in this exceptional patient group.
There are significant unmet needs for just about every clinical aspect of the patient with 
cluster headache, particularly related to the severity of the disease and treatment options. Most 
patients experiencing cluster headache attacks rate their pain intensity as near to or at the 
worst pain imaginable (using a Visual Analog Scale 10 cm scale).6
Due to the high unmet need for new, effective, fast onset and better tolerated therapies for 
episodic cluster headache, Lundbeck is planning to conduct this global Phase III clinical 
study.34 The study will allow the evaluation of treatment effects, including safety, and is 
intended to show a statistically significant effect on number of attacks during the cluster 
headache bout. The results from the Phase III study with galcanezumab in episodic cluster 
headache,35 and its approval by the FDA in this indication, prove the principle that mAbs, 
targeting CGRP, provide clinical benefit in episodic cluster headache. Thus eptinezumab, 
which has similar biological properties and a documented faster onset of action in patients 
with migraine, is considered a viable therapeutic option to provide a fast reduction in the 
number of cluster headache attacks in patients with episodic cluster headache. 
2
Objectives and Endpoints
The study objectives and endpoints are summarized in Panel 3.
Panel 3
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To evaluate the efficacy of 
eptinezumab in patients with eCH
Primary endpoint:
Change from Baseline in the number of weekly attacks (Weeks 1–2)
Key secondary endpoints:
Response: 50% reduction from Baseline in the number of weekly 
attacks (Weeks 1-2)
Change from Baseline in the number of weekly times an abortive 
medication was used (Weeks 1-2) 
Change from Baseline in the number of daily attacks (Days 1-3)
Change from Baseline in the number of weekly days with < 
3attacks per day (Weeks 1-2)
Time from first infusion of IMP to resolution of cluster headache 
bout (within the first 4 weeks)
Number of attacks starting <= 24 hours after the start of the first 
infusion of IMP
Secondary endpoints:
Change from Baseline in the daily mean score on 5-point self-
rating pain severity scale (Days 1- 3)
Change from Baseline in the number of weekly attacks (Week 1)
Change from Baseline in the number of weekly attacks (Week 2)
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 34 of 112
Objectives
Endpoints
Response: 50% reduction from Baseline in the number of weekly 
attacks (Week 1)
Response: 30% reduction from Baseline in the number of weekly 
attacks (Week 1)
Response: 30% reduction from Baseline in the number of weekly 
attacks (Weeks 1-2)
Change from Baseline in the weekly integrated measure of 
frequency and intensity of pain (Weeks 1-2) (that is, the sum of the 
intensity (worst pain on a 5-point self-rating pain severity scale) for 
each attack during that week)
Change from Baseline in the weekly integrated measure of 
frequency and intensity of pain (Week 1) (that is, the sum of the 
intensity (worst pain on a 5-point self-rating pain severity scale) for 
each attack during that week).
Change from Baseline in the weekly integrated measure of 
frequency and intensity of pain (Week 2) (that is, the sum of the 
intensity (worst pain on a 5-point self-rating pain severity scale) for 
each attack during that week)
Change from Baseline in the number of weekly attacks 
(Weeks 1- 4)
Change from Baseline in the weekly integrated measure of 
frequency and intensity of pain (Weeks 1-4) (that is, the sum of the 
intensity (worst pain on a 5-point self-rating pain severity scale) for 
each attack during that week).
Change from Baseline in the mean score on 5-point self-rating pain 
severity scale (average per attack over a week) for each of Weeks 
1, 2, 3, and 4
Change from Baseline in the number of weekly attacks for each of 
Weeks 3 and 4
Patient Global Impression of Change (PGIC) score at each of 
Weeks 1, 2, and 4 
Change from Baseline in the Sleep Impact Scale (SIS) domain 
scores at each of Weeks 2 and 4
Exploratory endpoints:
Response: 75% reduction from Baseline in the number of weekly 
attacks (Weeks 1-2)
Change from Baseline in the number of weekly times an abortive 
medication was used (Weeks 1-4)
Time from first infusion of eptinezumab to resolution of cluster 
headache bout (within the first 16 weeks; only for patients 
randomized to eptinezumab at Baseline) 
Use (yes/no) of abortive medication (triptans or O2) for each of 
Weeks 5 to 16
Use (yes/no) of preventive medication for each of Weeks 1 to 16
Use (yes/no) of transitional treatment for each of Weeks 5 to 16
Number of attacks starting <= 24 hours after the start of the first 
infusion of IMP divided into three parts: one for attacks starting >0 
and <= 8 hours after the start of the first infusion of IMP, one for 
attacks starting >8 and <=16 hours after the start of the first 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 35 of 112
Objectives
Endpoints
infusion of IMP, and one for attacks starting >16 and <=24 hours 
after the start of the first infusion of IMP
Change from Baseline in the EQ-5D-5L Visual Analogue Scale 
(VAS) score at Weeks 8 and 16 
Patient Global Impression of Change (PGIC) score at Weeks 8 and 
16 
Number of weekly attacks for each of Weeks 5 to 16
Severity of pain (average per attack over a week) based on a 5-
point self-rating pain severity scale for each of Weeks 5 to 16
Secondary Objectives
To evaluate the efficacy of 
eptinezumab on health-related quality 
of life, health care resource utilization, 
and work productivity 
Secondary endpoints:
Change from Baseline in EQ-5D-5L Visual Analogue Scale (VAS) 
at Weeks 2 and 4
Health Care Resources Utilization (HCRU) at Baseline and 
Week 4
Change from Baseline in the Work Productivity Activity 
Questionnaire: General Health second version (WPAI:GH2.0) sub-
scores (Absenteeism, Presenteeism, Work productivity loss, 
Activity impairment) at Week 4
Safety Objectives
To evaluate the safety and tolerability 
of eptinezumab
Safety Endpoints:
Adverse events
Absolute values and changes from baseline in clinical safety 
laboratory test values, vital signs, weight, and ECG parameter 
values
Potentially clinically significant clinical safety laboratory test 
values, vital signs, weight changes, and ECG parameter values
Development of specific anti-eptinezumab antibodies (ADA) 
including neutralizing antibodies (NAbs)
Columbia-Suicide Severity Rating Scale (C-SSRS) score
3
Study Design
3.1
Overview of the Study Design
This study has been designed in accordance with the Declaration of Helsinki.36
This is an interventional, multi-regional, randomized, double-blind, placebo-controlled 
delayed-start study, designed to demonstrate the efficacy and safety of eptinezumab in 
patients with episodic Cluster Headache (eCH).
This study will be conducted in compliance with the protocol, Good Clinical Practice,37 and 
applicable regulatory requirements.
An overview of the study is presented in Panel 1.
304 patients will be randomly allocated via a randomization system to one of the two initial 
treatments: eptinezumab 400 mg, or placebo, in a ratio of 1:1 (152 patients in the eptinezumab 
400 mg group and 152 patients in the placebo group). The randomization has been stratified 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 36 of 112
by country as the number of patients (app. 300) compared to the number of sites (>100) 
would yield a number of sites with very few patients (and therefore an imbalance in the 
randomization between the two sequences) if the stratification was done by site.
The target population for this study is defined as patients with eCH, based on the IHS ICHD-3 
classification, with an adequately documented record or reliable history of eCH prior to 
Screening Visit 1 and confirmed via prospectively collected information in the eDiary during 
Screening Period 2. The study is planned as a global study.
The total study duration from Screening Visit 1 to the Safety Follow-up Visit is 
approximately 77 weeks and includes Screening Period 1 (approximately 12 months / 
52 weeks), Screening Period 2 (7 days), a Placebo-controlled Period (4 weeks), an Active 
Treatment Period (4 weeks), a Post-treatment Observational Period (8 weeks) and a Safety 
Follow-up Period (8 weeks).
The patients can be screened up to 12 months prior to the Screening Period 2. The patients 
will enter Screening Period 2 as soon as possible after they experience the beginning of a 
cluster headache bout, which is characterized by the presence of at least one typical cluster 
headache attack, and not later than 1 week after the start of the first attack. Under exceptional 
circumstances, when a patient is able to attend Screening Visit 2 only during the second week 
after the first typical cluster headache attack, the possibility to enrol this patient in the study 
will be discussed with the investigator and the decision will be taken in the context of known 
history of typical duration of the bout for the individual patient.
Eligible patients will be randomly assigned to receive at the Baseline Visit (Day 0/Visit 3) 
either eptinezumab 400 mg or placebo, administered as an IV infusion over 45 minutes 
(+15 minutes). Preferably the infusion should be administered in the morning. 
All patients will continue in the Active Treatment Period of the study and will receive a 
second IMP infusion (eptinezumab 400 mg or placebo), administered as an IV infusion over 
45 minutes (+15 minutes), at the end of Week 4 (Visit 6) in a blinded manner, so that patients 
previously exposed to eptinezumab will receive placebo and patients randomized to placebo 
will receive eptinezumab 400 mg.
The Safety Follow-up Visit will take place at Week 24 (Visit 10), 20 weeks (5 half-lives) after 
the second IMP administration. 
Unless otherwise specified, the Active Treatment Period, the Post-treatment observational 
Period, and the Safety Follow-up Period will be reported as one period called the Delayed 
Start Period.
Patients who withdraw from the study, except for those who withdraw their consent, will be 
asked to attend a Withdrawal Visit as soon as possible and a further Safety Follow-Up Visit 
(SFU), scheduled 20 weeks (5 half-lives) after the last IMP administration.
Eligibility will be assessed during Screening Period 1, during Screening Period 2, as well as 
before the administration of IMP at the Baseline Visit (Day 0/Visit 3) as described in Panel 2. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 37 of 112
The following visits will be site visits: Screening Visit 1, Screening Visit 2, Baseline Visit 
(First Visit of the Placebo-controlled Period (Day 0/Visit 3) (randomization and IMP 
infusion)), Last Visit of the Placebo-controlled Period, at the end of Week 4 (Visit 6-second 
IMP infusion), Completion Visit at Week 16 (Visit 9) and SFU Visit at Week 24 (Visit 10) or 
Withdrawal Visit, if applicable. All other study visits will be phone contact visits.
In exceptional situations, such as where COVID-19 pandemic restrictions impact the ability to 
perform site visits, site visits may only consist of blood sampling and urine sampling (for 
clinical laboratory tests, exploratory eptinezumab quantification, ADA including Nab, and 
exploratory biomarkers), ECG, vital signs, physical and neurological examinations, adverse 
event recording, and IMP administration, while the remaining assessments (eDiary, ePROs, 
C-SSRS, and investigator evaluations) can be conducted remotely via a virtual clinic visit.
These cases must be approved by the CRO’s medical monitor.
Patients will be assigned an eDiary at the Screening Visit 2 and will be required to complete 
this daily from the time of Screening Visit 2 until the Completion Visit (Week 16/Visit 9) or 
until the Withdrawal Visit. 
During the study visits with IMP infusion, safety assessments will be performed before and 
after the infusion. At these visits, AEs as well as safety laboratory tests, ECG, weight, and 
vital signs, including body temperature, will be collected. Electronic patient-reported 
outcomes (ePROs) must be completed prior to infusion.
Blood samples for IMP quantification will be collected at regular intervals during the study 
(Panel 2) and results will be reported separately. 
Patients in the study will have access to appropriate medical care in accordance with normal 
clinical practice after they complete or withdraw from the study.
Assessments performed in a subset of patients:
Blood sampling for pharmacogenetics is optional. Refer to Panel 2.
Interim Analysis:
An interim futility analysis that is unblinded to a study independent team, evaluating efficacy, 
will be performed based on 204 randomized and treated patients who have had the chance of 
completing the Visit 6 (Week 4). Randomized patients with an infusion on the same date, but 
after 204 patients have been treated, will also be included. The interim analysis will be 
performed for the APTS_IN. If the estimated treatment effect is less than 1/3 of the expected 
effect size (3.00/3 = 1), a decision will be made to either continue the recruitment, or to end 
enrolment.
The interim analysis will be performed by an independent CRO.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 38 of 112
The independent CRO will inform a predefined group of Lundbeck employees whether the 
criterion for the interim futility have been met or not. No further details of the interim analysis 
results will be provided.
Details of information flow and the interim process will be described in a separate interim 
analysis charter.
Details of the statistical analysis for the interim analysis will be described in an interim 
statistical analysis plan.
3.2
Rationale for the Study Design
The current study is planned as a placebo-controlled study with delayed-start design. It
includes a 4-week double-blind, randomized Placebo-controlled Period to investigate whether 
eptinezumab can lead to clinically significant improvement in patients with episodic cluster 
headache. The duration of the Placebo-controlled Period and the selection of the time for the 
primary outcome measure is in line with the Guidelines of the International Headache Society
for controlled trials of drugs in cluster headache38 and is based on the published results with 
galcanezumab in episodic cluster headache.35 All patients will continue in the Active 
Treatment Period of the study and will receive a second IMP infusion (placebo or 
eptinezumab 400 mg) in a blinded manner, so that patients previously exposed to 
eptinezumab will receive placebo and patient randomized to placebo will receive eptinezumab
400 mg. Thus, the delayed-start design provides an opportunity for all study participants to 
receive treatment with eptinezumab. The duration of Screening Period 1 is chosen, based on 
the natural history of the disease and is intended to ensure that patients with a history of 
episodic cluster headache progress to Screening Period 2 in the moment they enter in a cluster 
bout and reach the required level of cluster headache attacks activity. The Screening Period 2
duration is chosen to allow (i) enough time for collection of prospective data on cluster 
headache activity and (ii) enrolment of patients who are predicted to still be in a bout for at 
least six more weeks. 
The proposed study population for this study are patients with episodic cluster headache in a 
bout. This target population corresponds largely to the patient population in the completed 
Phase III study with galcanezumab in which galcanezumab demonstrated positive 
benefit / risk profile and is considered representative for patients with episodic cluster 
headache in need of treatment.35
The primary endpoint is the change from Baseline in the number of weekly attacks 
(Weeks 1-2) and will be evaluated at Week 2. Based on the Guidelines of the International 
Headache Society for controlled trials of drugs in cluster headache,38 the published results 
with galcanezumab in episodic cluster headache35 and the documented faster onset of action 
of eptinezumab in patients with migraine, this is expected to be an adequate duration to 
investigate the efficacy of eptinezumab. Secondary endpoints evaluating the effect on speed 
of onset, sleep disturbances, health-related quality of life, as well as work productivity, are 
included in the study to evaluate the impact of treatment beyond the reduction in number of 
cluster headache attacks. The sample size for the primary endpoint is chosen based on the 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 39 of 112
phase III data with galcanezumab in patients with episodic cluster headache and should 
provide adequate power for detection of a clinically meaningful treatment effect. An interim 
futility analysis that is unblinded to a study independent team, evaluating efficacy, will be 
performed based on 204 randomized and treated patients who have had the chance of 
completing the Visit 6 (Week 4/). Randomized patients with an infusion on the same date, but 
after 204 patients have been treated, will also be included. Based on the interim analysis result 
of the primary endpoint, a decision will be made to either continue the recruitment, or to end 
enrolment.
Fulfilment of criteria for eCH, according to the eligibility criteria in this protocol, will be 
confirmed via prospectively collected information in the eDiary during the Screening period 2 
(i.e., frequency of minimum 7 and maximum of 56 CH attacks for the 7-day Screening 
Period 2). The lower and the upper limit for CH attack frequency is in line with the IHS 
ICHD-3 criteria for CH. Clinical site staff will be given access to the eDiary data. Prior to 
enrolment, the investigator will review the data in the eDiary Eligibility Report to determine if 
the eligibility criteria are fulfilled. 
The dose of 400 mg eptinezumab is recommended, based on the fact that cluster headache 
patients have higher CGRP-levels compared to migraine patients and healthy controls,21
suggesting that a higher dose of eptinezumab is needed to alleviate features of the disease, 
related to the CGRP pathobiology. This is in line with the design of the galcanezumab trial in 
episodic cluster headache35 which investigated the efficacy and safety of a dose, higher, 
compared to the approved galcanezumab dose for the treatment of migraine.39,40
The placebo group is representative of the best supportive care (BSC) as the study allows 
abortive therapy for cluster headache. Thus, the study will compare the efficacy of 
eptinezumab and BSC versus BSC alone.
During the Placebo-controlled Period of the study the patients will be randomly allocated to 
one of two treatment arms of either 400 mg eptinezumab, or placebo with a randomization 
ratio of 1:1. Inclusion of a placebo group is justified since the group is representative of the 
best supportive care (BSC), allowing abortive therapy of the cluster headache attack. Thus, 
the study will compare the efficacy of eptinezumab and BSC versus BSC alone. All patients 
will continue in the Active Treatment Period of the study and will receive a second IMP 
infusion (placebo or eptinezumab 400 mg) in a blinded manner, so that patients previously 
exposed to eptinezumab will receive placebo and patient randomized to placebo will receive 
eptinezumab 400 mg. Given the eptinezumab half-life and proven efficacy over 12 weeks in 
migraineurs, all patients will be exposed to eptinezumab during the Active Treatment Period. 
Preventive treatments (transitional and maintenance) can be initiated after the end of the 
Placebo-controlled Period; hence no patient will be denied access to standard treatments in 
this study.
Blood sampling will be required at several time points during the study to evaluate standard 
safety laboratory parameters, ADA including NAbs.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 40 of 112
3.3
Benefit-Risk Assessment
Benefits
It has been shown that mAbs targeting CGRP provide clinical benefit in patients with episodic 
cluster headache.35 Therefore, eptinezumab, which is also a mAb targeting CGRP with 
documented fast onset of action in patients in need of preventive treatment for migraine, is 
considered a viable therapeutic option to provide a fast reduction in the number of cluster 
headache attacks in patients with eCH. The intravenous formulation offers a route of 
administration with 100% bioavailability that allows for rapid CGRP inhibition.
Risks
No safety data, specific to the use of eptinezumab in patients with cluster headache is 
available. However, the safety of eptinezumab has been investigated in over 2,400 healthy 
subjects and patients with migraine at doses up to 1000 mg and the analyses show that 
eptinezumab is safe and well tolerated (see the current version of the Investigator’s 
Brochure24 for more detailed information). No important identified risks or important 
potential risks that could alter the benefit-risk profile of eptinezumab have been identified to 
date. Nasopharyngitis and hypersensitivity reactions, including anaphylactic reactions, are 
considered adverse reactions for eptinezumab. In the pivotal studies in migraine, 
hypersensitivity reactions were reported with multiple related adverse event terms, such as 
hypersensitivity, angioedema, urticaria, flushing/hot flush, rash and pruritus. Most 
hypersensitivity reactions occurred during the infusion and were not serious. Serious 
hypersensitivity reactions have been reported, including anaphylactic reactions on rare 
occasions. In all cases, the patients recovered upon standard of care treatment.
With regard to the safety of the eptinezumab 400 mg dose, the safety of eptinezumab in 
patients with migraine and in healthy subjects has been explored at doses up to 1000 mg, with 
no observable difference in the safety profile compared to the eptinezumab 100 mg and 
300 mg doses, which are the doses approved by the US FDA and in Canada for preventive 
treatment of migraine. In addition, the long-term treatment effects of eptinezumab 400 mg 
will be evaluated in an open-label study in patients with chronic Cluster Headache (study 
19385A).
The safety of study subjects is monitored throughout the study via periodic collection of 
adverse events, vital signs, laboratory tests, ECGs and other safety assessments such as 
evaluation of the suicidality (C-SSRS). Although there was no evidence of impact of ADA 
development on efficacy or safety in any of the previous clinical studies, in the current study 
blood sampling for ADA including NAbs will be assessed prior to the first eptinezumab 
infusion, at Weeks 16 and 24 (Safety Follow-up), and at Withdrawal Visit when applicable. 
To monitor patient safety, safety data will be reviewed on an ongoing basis and evaluated 
regularly by the Lundbeck Safety Committee. This will ensure that prompt actions are taken, 
if needed.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 41 of 112
Risk-mitigation
Based on the biological plausibility and the inherent risk, hypersensitivity reactions are 
possible with any infused protein.41 In order to minimize the risk of hypersensitivity reactions 
due to the higher dose of eptinezumab (400 mg considered justified in patients with cluster 
headache based on the higher CGRP levels) compared to doses used in migraine (100 mg or 
300 mg), the minimum duration of the eptinezumab infusion must be 45 minutes 
(45 + 15 minutes, according to the study protocol).
Furthermore, eptinezumab is administered in a clinical facility at the study site under medical 
supervision with appropriate measures for adequate treatment in place. Per protocol, patients 
are required to be monitored during the infusion and for a period of 1 hour from the end of 
infusion. Patients will be requested to stay longer should the investigator determine this is 
clinically warranted.
In addition to the above, the following risk mitigations are also taken for hypersensitivity 
reactions:

History of severe drug allergy or hypersensitivity or known hypersensitivity to 
IMP/excipients is an exclusion criterion.

Serious/severe hypersensitivity is a criterion for withdrawal from treatment.
In the context of the coronavirus disease 2019 (COVID-19), Lundbeck and the CRO will 
continue to follow each participating country’s guidance for travel, social distancing, 
minimum number of people in an indoor location at any time, personal protective equipment, 
and remote consenting procedures. Should further restrictions be imposed in any country that 
could impact patients’ ability to attend visits, and/or clinical site staff’s ability to continue to 
resource the study to an adequate level, Lundbeck and the CRO will adapt their approach to 
patient enrolment and return visits. These mitigations may include, but not limited to:

Including a home nursing vendor to ensure the continuation of IMP Visits, including 
eptinezumab administration and post-infusion monitoring (if logistically possible and 
acceptable by the country-specific law). The administration via the home nursing vendor 
will have the same medical supervision and equipment/treatment in place needed to ensure 
patient’s safety as similar to the clinical facility at the study site.

Risk assessment (per country or site level) of enrolling new patients.
Benefit-Risk Assessment
Cluster headache is an excruciatingly painful primary headache disorder, which places an 
exceptional burden on those affected. There are significant unmet needs for the patient with 
cluster headache, particularly related to the severity of the disease and the lack of available 
fast onset, and better tolerated therapies.
The safety of eptinezumab, as investigated in patients with migraine and in healthy 
volunteers, shows that eptinezumab is safe and well tolerated. The risks for study subjects are 
further mitigated by measures in the protocol and safety monitoring of study subjects 
throughout the study.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 42 of 112
Sponsor considers the benefit-risk profile of Study 19386A to be acceptable based on the 
nonclinical and clinical data for eptinezumab.
4
Ethics
4.1
Ethical Rationale
This study will evaluate eptinezumab as a potential therapeutic candidate for a target patient 
population with episodic cluster headache in a bout. 
Inclusion of placebo group is justified since the group is representative of the best supportive 
care (BSC). During the Placebo-controlled Period of the study patients will be randomly 
allocated to one of two treatment arms of either 400 mg eptinezumab, or placebo with a 
randomization ratio of 1:1. Inclusion of a placebo group is justified since the group is 
representative of the BSC, allowing abortive therapy of the cluster headache attack. Thus, the 
study will compare the efficacy of eptinezumab and BSC versus BSC alone. All patients will 
continue in the Active Treatment Period of the study and will receive a second IMP infusion 
(placebo or eptinezumab 400 mg) in a blinded manner, so that patients previously exposed to 
eptinezumab will receive placebo and patient randomized to placebo will receive eptinezumab
400 mg. Given the eptinezumab half-life and proven efficacy over 12 weeks in migraineurs, 
all patients will be exposed to eptinezumab during the Active Treatment Period. Transitional 
and preventive therapies can be initiated after the end of the Placebo-controlled Period; hence 
no patient will be denied access to standard treatments in this study.
The dose of 400 mg eptinezumab is recommended, based on the fact that cluster headache 
patients have higher CGRP-levels compared to migraine patients and healthy controls,21
suggesting that a higher dose of eptinezumab is needed to alleviate features of the disease, 
related to the CGRP pathobiology. This together with data from previous studies,24 in which 
eptinezumab was dosed up to 1000 mg and without any major safety findings, support that 
eptinezumab 400 mg can be safely used in the current study. The published results of the 
galcanezumab trial in episodic cluster headache35 which investigated the efficacy and safety 
of a dose, higher, compared to the approved galcanezumab dose for the treatment of migraine 
do not suggest any safety concerns and provide further support for the dose selection.39,40
The patients will be fully informed about the study, including the risks and benefits of their 
participation in the study.
The patient may withdraw from the study at any time, for any reason, specified or unspecified 
and without penalty or loss of benefits to which the patient is otherwise entitled. Unscheduled 
visits can be made, and immediate withdrawal is possible. Throughout the study, signs of 
suicidal risk will be assessed and the patients at risk will be withdrawn from the study.
In general, safety data with eptinezumab have not raised any clinical safety concerns from the 
completed phase III studies in migraine. However, it cannot be ruled out that the IMP could 
have adverse effects that have not yet been reported. Blood sampling will be required at 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 43 of 112
several time points during the study to evaluate standard safety laboratory parameters. 
Although there was no evidence of impact of ADA development on efficacy or safety in any 
of the previous clinical studies, in the current study the ADA response will be assessed prior 
to the first IMP infusion, at Weeks 16 and 24 (Safety Follow-up). To monitor patient safety, 
safety data will be reviewed on an on-going basis and evaluated regularly by the Lundbeck 
Safety Committee. This will ensure that prompt actions are taken, if needed. 
The risks associated with this study are considered adequately elucidated in the nonclinical 
and clinical studies, well controlled by cautionary measures in the study design, and well-
balanced with the potential benefits of the treatment with eptinezumab, a potentially effective 
treatment for episodic cluster headache.
In accordance with Good Clinical Practice,37 qualified medical personnel at Lundbeck or the 
clinical CRO will be readily available to advise on study-related medical questions. Medical 
monitoring will be performed throughout the study. Safety data will be reviewed regularly by 
the Lundbeck Safety Committee to ensure that prompt action is taken, if needed.
In accordance with Good Clinical Practice,37 the investigator will be responsible for all 
study-related medical decisions.
Information on race will be collected, if allowed according to the country-specific law.
Collecting information on race will allow the evaluation of treatment effects including safety 
evaluations in the overall population as well as investigations of the potential impact of 
intrinsic and extrinsic factors (as described in Ethnic Factors in the Acceptability of Foreign 
Clinical Data ICH E5(R1) Guideline).42
Risks Related to the Coronavirus Disease 2019
Sponsor and CRO have performed a review of the protocol, the participant population, and 
study design and conclude that the risks with regards to the COVID-19 are minimized both 
for patients participating in the study and clinical site staff conducting the study in line with 
the US FDA and EMA guidelines.43,44 The risks for the patients remain well controlled and 
balanced with the potential benefits of the treatment. This is based on the following:

Patients participating in the clinical study will not attend visits in an area of the hospital 
that would be high risk for COVID-19 patients to be treated or seen.

The protocol has flexibility for re-screening and Screening Period extension to further 
enable sites and patients to continue the trial in case of quarantine or lockdowns.

Patient visits to site will be limited to six on-site visits over a time span of 6 to 18 months 
(depending on the patient’s time of next bout) and all further contact will be conducted by 
phone. In exceptional situations, such as where COVID-19 pandemic restrictions impact 
the ability to perform site visits, site visits may only consist of blood and urine sampling 
(for clinical safety laboratory tests, exploratory eptinezumab quantification, ADA 
including NAb, and exploratory biomarkers), ECG, vital signs, physical and neurological 
examinations, adverse events recording, and IMP administration, while the remaining 
assessments (eDiary, ePROs, C-SSRS, and investigator evaluations) can be conducted 
remotely via a virtual clinic visit. Consequently, this reduces the burden on the clinical trial 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 44 of 112
site to manage recurring visits around the potential restrictions for number of people 
allowed on site at any one time.

Study allows the flexibility at Screening Visit 1 to allow for review and signature of 
Informed Consent Form(s) via virtual clinic visit and Screening Visit 1 assessments may 
be extended over several days, if needed. For other visits, patients are allowed to complete 
all their eDiary and ePROs in the remote setting (that is, at home), thus reducing the time 
that the patient needs to spend on site and minimizing burden for site staff at a given visit.

The percentage of on-site targeted source data verification required for the study is 
approximately 30%, which, along with the number of visits for this study, substantially 
decreases the amount of time clinical research associates (CRAs) are expected to spend on 
site. Further, remote source data verification is allowed in some cases as described in 
section 12.

Patients will be tested for COVID-19 as needed, according to country-specific 
requirements.
Sponsor and CRO will continue to follow each participating country’s guidance for travel, 
social distancing, minimum number of people in an indoor location at any time, personal 
protective equipment, and remote consenting procedures. Should further restrictions be 
imposed in any country that could impact patients’ and CRAs’ ability to attend visits, and/or 
clinical site staff’s ability to continue to resource the study to an adequate level, Sponsor and 
CRO will adapt their approach to patient enrolment, return visits and data monitoring by 
CRAs. These mitigations will include, but not limited to:

Including a home nursing vendor to ensure the continuation of IMP Visits (if logistically 
possible and acceptable by the country-specific law). The administration via the home 
nursing vendor will have the same medical supervision and equipment/treatment in place 
needed to ensure patient’s safety as similar to the clinical facility at the study site.

An adaptation of the on-site data monitoring scheme to increase remote monitoring and 
consideration of remote source data verification.

Risk assessment (per country or site level) of enrolling new patients.
Any adaptations to the already approved protocol procedures and monitoring approach will be 
implemented in line with the US FDA and EMA guidances.43, 44
Sponsor and CRO will assess on a site-by-site basis whether restrictions, either at a country or 
site level, would mean it would not be within the best interest of the potential patient or the 
clinical site staff to activate the study at a particular time point. This would be based on, but 
not limited to, the following:

Country/area lockdowns.

A site’s ability to undertake non-essential clinic visits.

A site’s ability to adequately resource the study.

CRO implemented restrictions for employee safety for travel and on-site visits.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 45 of 112
4.2
Informed Consent
No study-related procedures, including any Screening Visit 1 procedures, may be performed 
before the investigator has obtained written informed consent from the patient.
It is the responsibility of the investigator, or person designated by the investigator, to obtain 
written informed consent from the patient. If the informed consent process may be delegated, 
the requirements for the delegates must be documented prior to the start of the study. National 
laws must always be adhered to when allowing potential delegation. Any delegation must be 
documented in the site delegation log.
At Screening Visit 1, the patient will be asked to sign the:

Main Informed Consent Form

Informed Consent Form for blood sampling for pharmacogenetics (optional)
Under exceptional circumstances, such as where COVID-19 pandemic restrictions impact the 
ability to perform site visits, the discussion with the patients about the Informed Consent 
Form(s) can be done as a virtual clinic visit and the Informed Consent Form(s) can be 
provided remotely in line with the US FDA and EMA guidances.43, 44According to the EMA 
guidance, this could comprise contacting the patients via phone or video-calls and obtaining 
oral consents, to be documented in the patients' medical records, supplemented with email 
confirmation. Any consent obtained this way should be documented and confirmed by way of 
normal consent procedures at the earliest opportunity when the patients are back at the clinical 
sites.44
At Screening Visit 2, the patient will be asked to confirm consent by re-signing each of the 
Informed Consent Form(s) signed at Screening Visit 1 (separate signature lines on each form). 
If a patient does not enter a cluster bout during the maximum duration of Screening Period 1
(52 weeks), the site may request a 6-month extension of the Screening Period 1. If an 
extension is not requested or if an extension has been requested but not granted, the patient is 
considered a screen failure. If, after the 6-month extension has expired, the patient would still 
like to participate in the study and the study is still enrolling new patients, the patient is a 
screen failure and must sign new informed consent form(s) and will complete Screening 
Visit 1 again.
If the study completes enrolment or is terminated early due to the results of the interim 
analysis and the patient has not entered a cluster bout during Screening Period 1, the patient is 
considered a screen failure and will not be asked to attend any further study visits. If the study 
completes enrolment or is terminated early due to the results of the interim analysis and the 
patient is in Screening Period 2, the patient will continue in the study. 
Re-screening of Screening Visit 1 and re-screening or extension of Screening Visit 2 is 
allowed under certain circumstances. Refer to section 8.3.3, 8.3.4, and 8.3.5.
The investigator must identify vulnerable patients, that is, patients whose willingness to 
participate in this study might be unduly influenced by the expectation, regardless of whether 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 46 of 112
it is justified, of benefits associated with participation, or of a retaliatory response from senior 
members of a hierarchy in case of refusal to participate. Patients thus identified must be 
excluded from participation in the study.
Prior to obtaining written informed consent, the investigator or a designee must explain to the 
patients the aims and methods of the study and any reasonably expected benefits and 
foreseeable risks or inconveniences to the patients.
The patients must be informed:

that their participation in the study is voluntary and that they are free to withdraw from the 
study at any time without justifying their decision

of the possibility of withdrawing consent (section 8.9)

of their right to request a copy of their personal data from the study via the investigator

of their right to be informed by the investigator, after the study has been reported, about 
which treatment they received

of their right to receive information about the study results from the investigator on the 
patients’ own initiative; the results will be available approximately 1 year after the end of 
the study
The patients must be informed that persons authorized by Lundbeck and authorized personnel 
from certain authorities (domestic, foreign, data protection agencies, or ethics committees 
(ECs) or institutional review boards (IRBs)) may view their medical records. The patients 
must also be informed that de-personalized copies of parts of their medical records may be 
requested by authorized personnel from certain authorities (domestic, foreign, data protection 
agencies, or ECs or IRBs) for verification of study procedures and/or data. The confidentiality 
of the patients will in all cases be respected.
The patients must be given ample time and opportunity to enquire about details of the study 
prior to deciding whether to participate in the study.
It is the responsibility of the investigator to ensure that all questions about the study are 
answered to the satisfaction of the patients. Prior to allowing a patient to participate in the 
study, an Informed Consent Form(s) must be signed and dated by the patient and signed and 
dated by the investigator or a designee on the same day. The patients must be given a copy of 
the written information (Patient Information Sheet) as well as a copy of the signed Informed 
Consent Form(s).
The consent procedures described above will only be implemented if allowed by local law 
and regulations and will only be initiated after approval by the relevant ECs or IRBs.
As the blood sampling for the exploratory genomic, proteomic, and metabolomic analyses, 
including blood sampling for possible future ADA assessment and future exploratory 
biomarkers, is an integral part of this study, the main Informed Consent Form covers these 
analyses. Conversely, the blood sampling for pharmacogenetics is optional and a separate 
Informed Consent Form covers this analysis. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 47 of 112
The blood samples for potential future exploratory biomarker analysis, or the data derived 
from these blood samples, may be shared with academic and public institutions and other 
companies. However, Lundbeck will retain full control of the samples and their use in 
accordance with the information in the Informed Consent Form and a Material Transfer 
Agreement.
Country-specific pregnancy ICF: see section 10.2.
A patient may, at any time and without stating a reason, specifically request the destruction of 
the patient’s DNA sample, irrespective of the patient’s continued participation in the study.
The investigator must send a written request on behalf of the patient to the International Study 
Manager. The investigator will receive written confirmation from Lundbeck when the DNA 
sample has been destroyed.
4.3
Personal Data Protection
The data collected in this study will be processed in accordance with the specifications 
outlined in the Danish Data Protection Act and the European Union legislation45 to ensure that 
requirements regarding personal data protection are met. If an external organization will 
process data on behalf of Lundbeck, a contractual procedure will be signed between 
Lundbeck and the external organization to ensure compliance with the above-mentioned 
legislation.
4.4
Ethics Committees and Institutional Review Boards 
This study will be conducted only after Lundbeck has received confirmation that the 
regulatory authorities have approved or confirmed notification of the study and that written 
approval of the protocol has been granted by the appropriate EC or IRB.
The investigator must not allow any patients to participate in the study before receiving 
confirmation from Lundbeck or the CRO that the required approvals and/or notifications have 
been received.
The EC or IRB must be informed when specific types of protocol amendments have been 
made and written approval must be obtained before implementation of each amendment, if 
required by local law.
If applicable, interim reports on the study and reviews of its progress will be submitted to the 
EC or IRB by the investigator at intervals stipulated in its guidelines.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 48 of 112
5
Study Population
5.1
Number of Patients and Regions
Planned regions:
Europe, North America, and Japan
Planned number of screened patients (approximately): 
760
Planned number of randomized patients:
304
5.2
Patient Recruitment
Competitive patient recruitment between sites will be used during the entire recruitment 
period to ensure that the required number of patients are randomized within the planned 
recruitment period.
The investigators will be notified immediately when the recruitment period comes to an end.
When the study completes enrolment or if the study is terminated early due to the results of 
the interim analysis, any patients who are in Screening Period 1 will be considered a screen 
failure and will not be asked to attend any further study visits and any patients who are in the 
Screening Period 2 will continue in the study.
5.3
Selection Criteria
Patient selection is based on the inclusion and exclusion criteria listed below.
Patients who meet inclusion criteria 1, 2, 4, 5, 6, 7, 8, 9, 10, 11, 15, 18 and none of exclusion 
criteria 1, 2, 4, 5, 6, 7, 8, 9 (At Screening Visit 1 the investigator must consider excluding 
patients with a lifetime history of psychosis, bipolar mania, or dementia. Patients with other 
psychiatric conditions, whose symptoms at Screening Visit 1, are not controlled or who have 
not been adequately treated must be identified and the investigator should consider initiation 
of appropriate treatment as medically indicated), 10, 11, 12, 13, 14 (Patients with uncontrolled 
hypertension at Screening Visit 1, must be identified and the investigator must consider 
initiation of appropriate treatment as medically indicated), 15, 16, 17, 20, 24, 25, 26, 27, 28, 
29 at Screening Visit 1 are eligible to enter the Screening Period 1.
The eligibility of patients who occasionally use cannabinoids (confirmed by either anamnesis 
or finding at Urine drug screen at Screening Visit 2) must be based on a confirmation from the 
investigator that the patient does not meet Exclusion criteria 10, 24 and 25.
Patients who meet each of the inclusion criteria and none of the exclusion criteria at the
Screening Visit 2 and Baseline Visit (Day 0/Visit 3) are eligible to participate in this study.
Refer to Panel 2.
Inclusion Criteria
1.
The patient is able to read and understand the Informed Consent Form(s).
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 49 of 112
2.
The patient has signed the Informed Consent Form(s).
3.
[Inclusion Criterion 3 removed from protocol edition 2.0].
4.
The patient is willing and able to attend study appointments within the specified time 
windows.
5.
The patient is an outpatient.
6.
The patient has adequate venous access for administration of study drug.
7.
The patient has episodic cluster headache, as defined by IHS ICHD-3 classification,1 (see 
section 9.1.2) with an adequately documented record or reliable history of eCH of at least 
12 months prior to Screening Visit 1.
8.
The patient has a medical history of first symptoms of cluster headache from <60 years of 
age.
9.
The patient has an adequately documented record or reliable history of previous acute and 
preventive medication use for eCH, for at least 12 months prior to Screening Visit 1.
10. The patient has a prior history of cluster period(s) lasting 6 weeks or longer, when 
untreated.
11. The patient is able to distinguish cluster headache attacks from other headaches (i.e. 
tension-type headaches, migraine).
12. The patient is, at Screening Visit 2, in cluster headache bout, characterized by the 
presence of at least one typical cluster headache attack, that started not later than 1 week
prior to Screening Visit 2. In the opinion of the investigator the cluster headache bout is 
likely to continue for at least another 6 weeks based on prior cluster period history. Under 
exceptional circumstances, when a patient is able to attend Screening Visit 2 only during 
the second week after the first typical cluster headache attack, the possibility to enroll this 
patient in the study will be discussed with the investigator and the decision will be taken 
in the context of known history of typical duration of the bout for the individual patient. 
13. The patient has during Screening Period 2 based on prospectively collected information 
in the eDiary a weekly cluster headache attack frequency of a (this requirement should 
not be shared with the patient):
minimum of at least 7 total cluster headache attacks out of the 7-day Screening 
Period 2
maximum of 56 cluster headache attacks out of the 7-day Screening Period 2
14. The patient has demonstrated compliance with the eDiary by entry of data for at least 6 of 
the 7 days of Screening Period 2.
15. The patient is aged ≥18 and ≤75 years at Screening Visit 1.
16. The patient, if a woman, must:
have had her last natural menstruation ≥12 months prior to Screening Visit 1, OR
have been surgically sterilized prior to Screening Visit 1, OR
have had a hysterectomy prior to Screening Visit 1, OR
remain sexually abstinent, when this is in line with her preferred and usual lifestyle, 
OR
engage exclusively in same-sex relationships, OR
agree not to try to become pregnant during the study, AND
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 50 of 112
use at least one of the below adequate contraception: 
o
combined oral, intravaginal or transdermal hormonal contraception
o
progestogen-only oral, injectable or implantable hormonal contraception
o
intrauterine devices (IUD) 
o
intrauterine hormone-releasing system (IUS) 
o
barrier methods (such as male or female condom) with spermicide
o
vasectomized partner 
The contraception must be used from Screening Visit 1 to ≥6 months after the last 
dose of IMP.
17. The patient, if female, must have a confirmed negative blood pregnancy test at Screening 
Visit 2.
18. The patient agrees to have regular contact with another adult throughout the study (in the 
Czech Republic only).
[Country Specific Amendment 1 for Japan; revision of inclusion criterion 16:
The patient, if a woman, must:
have had her last natural menstruation ≥12 months prior to Screening Visit 1, OR
have been surgically sterilized prior to Screening Visit 1, OR
have had a hysterectomy prior to Screening Visit 1, OR
remain sexually abstinent, when this is in line with her preferred and usual lifestyle, 
OR
engage exclusively in same-sex relationships, OR
agree not to try to become pregnant during the study, AND
use at least one of the below adequate contraception: 
o
combined oral, intravaginal or transdermal hormonal contraception
o
progestogen-only oral, injectable or implantable hormonal contraception
o
intrauterine devices (IUD) 
o
intrauterine hormone-releasing system (IUS) 
o
male or female condom with or without spermicide
o
cap, diaphragm or sponge with spermicide
o
vasectomized partner 
The contraception must be used from Screening Visit 1 to ≥6 months after the last 
dose of IMP.]
Exclusion Criteria
1.
The patient has previously been enrolled in this study and has received at least one IMP 
infusion.
2.
The patient has experienced failure on a previous treatment targeting the calcitonin 
gene-related peptide (CGRP) pathway (anti-CGRP mAbs and gepants).
3.
The patient has participated in a clinical study <30 days or has taken any investigational 
products within 5 plasma half-lives (whichever is longer) prior to Screening Visit 2. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 51 of 112
4.
The patient is a member of the study personnel or of their immediate families or is a 
subordinate (or immediate family member of a subordinate) to any of the study 
personnel.
5.
The patient is pregnant or breastfeeding.
6.
The patient has a history of severe drug allergy or hypersensitivity or known 
hypersensitivity or intolerance to the IMP or its excipients.
7.
The patient has confounding and clinically significant pain syndromes (for example, 
fibromyalgia, complex regional pain syndrome).
8.
The patient has a history or diagnosis of hypnic headache, hemicrania continua, new daily 
persistent headache, chronic migraine or unusual migraine subtypes such as hemiplegic 
migraine (sporadic and familial), recurrent painful ophthalmoplegic neuropathy, migraine 
with brainstem aura and migraine with neurological accompaniments that are not typical 
of migraine aura (diplopia, altered consciousness, or long duration).
9.
Patients with a lifetime history of psychosis, bipolar mania, or dementia are excluded. 
Patients with other psychiatric conditions whose symptoms are not controlled or who 
have not been adequately treated for a minimum of 6 months prior to Screening Visit 2
are also excluded.
10. The patient has a current diagnosis or history of substance abuse or alcohol abuse 
(DSM-5® criteria) <24 months prior to Screening Visit 2.
11. The patient has any other disorder for which the treatment takes priority over treatment of 
episodic cluster headache or is likely to interfere with study treatment or impair treatment 
compliance.
12. The patient has a history of moderate or severe head trauma or other neurological 
disorder or systemic medical disease that is, in the investigator’s opinion, likely to affect 
central nervous system functioning.
13. The patient has a history of cancer, other than basal cell or Stage 1 squamous cell 
carcinoma of the skin, that has not been in remission for >5 years prior to the first dose of 
IMP. Male patients with abnormal prostate-specific antigen (PSA) levels according to 
national/local guideline may be enrolled in the study provided they have been followed 
up, have been asymptomatic and have had no treatment for prostate cancer. Patients 
under surveillance for a low and stable level of M-component are allowed.
14. The patient has a history of clinically significant cardiovascular disease, including 
uncontrolled hypertension, ischaemia or thromboembolic events (for example, 
cerebrovascular accident, deep vein thrombosis, or pulmonary embolism).
15. The patient has or has had one or more of the following conditions that is/are considered 
clinically relevant in the context of the study: other neurological, pulmonary, hepatic, 
endocrinological, gastrointestinal, haematological, infectious, immunological or ocular 
disorder.
16. The patient has a history of epilepsy.
17. The patient takes or has taken recent or concomitant medication that is disallowed or 
allowed with restrictions (specified in Appendix II) or it is anticipated that the patient will 
require treatment with at least one of these medications during the study.
18. The patient has one or more clinically significant out-of-range vital signs at Screening 
Visit 2.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 52 of 112
19. The patient has a Body Mass Index (BMI) >39 kg/m2 at Screening Visit 2.
20. The patient has previously tested positive for human immunodeficiency virus (HIV), 
hepatitis B or hepatitis C.
21. The patient has one or more clinical laboratory test values outside the reference range, 
based on the blood and urine samples taken at Screening Visit 2, that are of potential risk 
to the patient’s safety, or the patient has, at Screening Visit 2:
a serum creatinine value >1.5 times the upper limit of the reference range
a serum total bilirubin value >1.5 times the upper limit of the reference range
a serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value 
>2 times the upper limit of the reference range
22. The patient has, at Screening Visit 2, an abnormal ECG that is, in the investigator’s 
opinion, clinically significant.
23. The patient is, at Screening Visit 2, at significant risk of suicide (either in the opinion of 
the investigator or defined, using the C-SSRS, as the patient answering: "yes" to suicidal 
ideation questions 4 or 5 or answering: "yes" to suicidal behaviour within the past
month). Patients who do not meet this criterion, but who are considered by the 
investigator to be at significant risk for suicide, are excluded.
24. The patient has a disease or takes medication that could, in the investigator’s opinion, 
interfere with the assessments of safety, or tolerability, or efficacy, or interfere with the 
conduct or interpretation of the study.
25. The patient is, in the investigator’s opinion, unlikely to comply with the protocol or is 
unsuitable for any reason.
26. The patient is hospitalized without consent or deprived of liberty due to a legal or 
administrative decision.
27. [Country-specific Protocol Amendment 1 for Czech Republic: The patient has poorly 
controlled hypertension, systolic blood pressure >160 mmHg and or diastolic blood 
pressure >100 mmHg.]
28. The patient is under legal guardianship and unable to provide his/her consent.
29. The patient is not covered by the national mandatory health insurance plan (when 
applicable according to country-specific law).
5.4
Withdrawal Criteria
A patient must be withdrawn from the study if:

the patient withdraws consent (defined as a patient who explicitly takes back his or her 
consent); section 8.9 states how the patient’s data will be handled

the patient has been randomized in error*

the patient fails to comply with study procedures 

the patient is lost to follow-up (defined as a patient who fails to comply with scheduled 
study visits or contact, who has not actively withdrawn from the study, and for whom no 
alternative contact information is available [this implies that at least two documented 
attempts have been made to contact the patient])
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 53 of 112

the patient is at significant risk of suicide (defined as answering "yes" to suicidal ideation 
questions 4 or 5 or answering "yes" to suicidal behaviour on the C-SSRS at any time 
during the study. Refer to Section 9.6.7.
A patient must be withdrawn from treatment if:

the investigator considers it, for safety, lack of efficacy, and/or study compliance reasons, 
in the best interest of the patient that he or she be withdrawn from treatment

any site personnel break the randomization code for that patient

the patient becomes pregnant

the patient has a serum ALT or AST value >3 times the upper limit of the reference range 
and a serum total bilirubin value >2 times the upper limit of the reference range

the patient has a serum ALT or AST value >5 times the upper limit of the reference range 
that is confirmed by testing <2 weeks later

the patient has a QTcF interval >500 ms; the decision to withdraw the patient may be 
postponed until a repeat ECG is taken, if it is taken within 24 hours

the patient experiences an anaphylactic reaction or another serious and/or severe 
hypersensitivity reaction to the eptinezumab infusion, as assessed by the investigator. If the 
event occurs during the infusion, the infusion must be discontinued immediately.
Patients who withdraw will not be replaced.
Patients who withdraw from the study, except for those who withdraw their consent, will be 
asked to attend a Withdrawal Visit as soon as possible and a further SFU Visit, scheduled 
20 weeks (5 half-lives) after the last IMP administration.
Patients who are withdrawn from the treatment will be given the opportunity to remain in the 
study at the discretion of the investigator. Patients will be expected to attend all scheduled 
study visits and procedures except IMP administration. If patients refuse, they will be asked to 
attend a Withdrawal Visit as soon as possible and a further SFU Visit, scheduled 20 weeks 
(5 half-lives) after the IMP administration.
*If patient has been randomized in error and has not been administered IMP, the patient must 
be withdrawn. Withdrawal of patients randomized in error and who have received IMP should 
be based on a case-by-case evaluation of the individual risk/benefit. The decision about the 
administration of the second dose of IMP will be based on an individual risk/benefit 
assessment as judged by the investigator. 
6
Investigational Medicinal Product (IMP) 
6.1
Treatment Regimen
Patients will be randomly allocated via a centralized randomization system to one of two 
dosing sequences in accordance with the randomization list in a ratio of 1:1 and dosed 
according to Panel 4.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 54 of 112
Panel 4
Dosing Schedule
Day/ End Week
A-B group
B-A group
Day 0/End week 0
400 mg eptinezumab
Placebo
Day 28/End week 4
Placebo
400 mg eptinezumab
The IMP will be administered at the Baseline Visit (Day 0/Visit 3) and at the end of Week 4
(Visit 6), by intravenous infusion over 45 minutes (+15 minutes)
6.2
IMP, Formulation, and Strength
The IMP supplied by Lundbeck in this study is: 

Eptinezumab 100 mg/ml (1ml/ vial) as Concentrate for Solution for Infusion. 
400 mg eptinezumab will be dispensed as 4 vials of 100 mg/ml (1ml/ vial), Concentrate for 
Solution for Infusion. 4 x 1 ml. of 100 mg/ml Concentrate for Solution for Infusion is added 
to 100 mL of 0.9% normal saline, intravenously. 
Placebo will be dispensed 100 mL of 0.9% normal saline, intravenously. 
The pharmacist or designee responsible for receiving, storing, preparing, and dispensing 
eptinezumab and placebo IV infusions will be unblinded and will not be responsible for other 
aspects of the clinical study where blinding is necessary.
The IV bags containing eptinezumab + saline and IV bags containing saline only will be 
identical in appearance.
Doses will be administered intravenously over a period of 45 (+15) minutes by the blinded 
investigator or designee. 
If the infusion is not completed or temporarily interrupted, the reason for the interruption 
must be recorded in the eCRF. If the investigator stops or pauses the infusion due to a 
potential safety or tolerability issue, an Adverse Event should be recorded.
Further instructions on preparation and procedures associated with administering the IV can 
be found in the Pharmacy Manual and Infusion Guidelines. 
6.3
Manufacturing, Packaging, Labelling, and Storage of IMP
The IMP will be manufactured, packaged, labelled, released (by a qualified person [QP]), and 
distributed in accordance with the principles of Good Manufacturing Practice, under the 
responsibility of Lundbeck.
The IMP will be provided in a patient kit containing 4 single-use vials (as a concentrate for 
solution for infusion).
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 55 of 112
The wording on the labels will be in accordance with Good Manufacturing Practice regarding 
labelling and national and/or local regulatory requirements. If additional information is to be 
added when the IMP is dispensed to the patients, this will be clearly stated on the labels, and 
the investigator will be instructed to do so.
No manipulation, repackaging, or relabelling of IMP is permitted after QP release by 
Lundbeck, unless a repackaging/relabelling agreement exists, and the documentation is 
available to Clinical Supply, H. Lundbeck A/S, and, where necessary, new QP releases are 
made.
The IMP will be identified using a unique kit IMP number.
The IMP must be stored in a safe and secure location, and in accordance with the storage 
conditions specified on the label.
6.4
Method of Assigning Patients to Treatment
Interactive response technology (IRT) will be used in this study. Each patient will be assigned 
a screening number by the IRT, and that number will be used to identify the patient 
throughout the study. When a patient is to be randomized, the investigator uses the IRT. The 
IRT allocates the patient to a treatment during the call and assigns the patient a randomization 
number in accordance with the specifications from Biostatistics, H. Lundbeck A/S.
6.5
IMP Accountability
IMP accountability is documented in the IRT by the unblinded site staff and monitored by the 
unblinded CRA.
The investigator and the pharmacist must agree to only dispense IMP to patients enrolled in 
the study. The investigator or the pharmacist must maintain an adequate record of the receipt 
and distribution of the IMP. This record must be available for inspection at any time.
6.6
Unblinding Procedures
Pharmacovigilance, H. Lundbeck A/S, and the investigator or the pharmacist (if applicable), 
will have access to the unblinded information for the double-blind treatment for each patient.
Access to these details will be via IRT.
The IRT unblinding procedure is described in the IRT User Guide.
The investigator may only break the code for a patient if knowledge of the IMP is necessary 
to provide optimal treatment to the patient in an emergency situation. If possible, the 
investigator should consult the CRA or CRO Medical Monitor before breaking the code. The 
investigator must record the date and reason for breaking the code on the IMP Code Break 
Form in the eCRF. If the emergency situation was an adverse event, it must be recorded on an 
Adverse Event Form. The CRA or CRO Medical Monitor must be notified immediately. The 
IRT will capture the date and time of the code break call. Information on the allocated 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 56 of 112
treatment will be provided during the call and by fax or email, depending on 
availability/preference. When the code is broken for a patient, the patient must be 
immediately withdrawn from the study. If this occurs during a visit, the investigator must 
complete the visit as a Withdrawal Visit; otherwise, the patient will be asked to attend a 
Withdrawal Visit.
7
Concomitant Medication
7.1
Concomitant Medication
Concomitant medication is any medication other than the IMP that is taken during the study
from three months prior to Screening Visit 2 up until the Safety Follow-up Visit. 
The concomitant medications that are disallowed or allowed with restrictions during the study 
are summarized in Appendix II.
Abortive therapy for cluster headache is allowed for the entire duration of the study (refer to 
list of therapies in Appendix II).
Some of the restrictions apply up until the end of the Placebo-controlled Period (Week 4) after 
which the patient can use transitional and preventive therapies for cluster headache. 
Details of all cluster headache therapies (prescription and over-the-counter) taken within 
12 months prior to Screening Visit 1 must be recorded in the eCRF at Screening Visit 1 and 
updated at Screening Visit 2, as / if applicable.
Details of all concomitant medication (prescription and over-the-counter) taken <3 months 
prior to Screening Visit 2 must be recorded in the eCRF at Screening Visit 2. Any changes 
(including reason for changes) in concomitant medication must be recorded at each 
subsequent visit.
For any concomitant medication for which the dose was increased due to worsening of a 
concurrent disorder after enrolment in the study, the worsening of the disorder must be 
recorded as an adverse event.
For any concomitant medication initiated due to a new disorder after enrolment in the study, 
the disorder must be recorded as an adverse event.
Use of Coronavirus Disease 2019 Vaccine
There is currently no data indicating that eptinezumab may interact with or impair the body´s 
immunological response to the COVID-19 vaccines. Hence, there are no indications for safety 
concerns of concomitant use of the COVID-19 vaccines with eptinezumab. As such, COVID 
19 vaccination is allowed during the eptinezumab studies with the guidance measures as 
described below.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 57 of 112
Patients must be allowed to receive their scheduled vaccination. If possible, a COVID-19 
vaccine should not be administered within 1 week prior to Screening Visit 2 and until the 
Primary Outcome Visit (Week 2). Furthermore, if possible, a COVID-19 vaccine should not 
be administered within ±3 days of the second IMP infusion at Week 4. If the patient has 
recently received a COVID-19 vaccine, the investigator should judge if the patient can be 
administered the IMP infusion at the scheduled visit based upon the patient’s individual 
response to the COVID-19 vaccine.
In the current study, if a patient is administered a COVID-19 vaccine (or any other 
prophylactic vaccine or other concomitant medication), this should be captured as 
concomitant medication in the eCRF, including the date that the vaccine was given. The name 
of the manufacturer and, if applicable, whether it was the “first” or “second” vaccination 
should also be added, in a bracket for example.
All adverse events, including those judged by the investigator to be related to the COVID-19 
vaccine, must be captured in the eCRF on the Adverse Event Form. A causality assessment, 
including an alternative causality as relevant, must be provided on the Adverse Event Form.
8
Study Visit Plan
8.1
Overview
An overview of the procedures and assessments to be conducted during the study and their 
timing is presented in Panel 2. Further details are in section 9.
Screening Visit 1 is performed up to 52 weeks prior to Screening Visit 2. The patient will 
attend Screening Visit 2 as soon as they are at the beginning of a cluster headache bout, which 
is characterized by the presence of at least one typical cluster headache attack, and not later 
than 1 week after the start of the first attack. Under exceptional circumstances, when a patient 
is able to attend Screening Visit 2 only during the second week after the first typical cluster 
headache attack, the possibility to enrol this patient in the study will be discussed with the 
investigator and the decision will be taken in the context of known history of typical duration 
of the bout for the individual patient. After Screening Period 2, the patient will attend the 
Baseline Visit (Day 0/Visit 3), which is the first visit of the Placebo-Controlled Period 
(randomization and IMP infusion). All patients will continue in the Active Treatment Period 
of the study and will receive a second IMP infusion (eptinezumab 400 mg or placebo) at the 
end of Week 4 (Visit 6). The Safety Follow-up Visit will take place at Week 24 (Visit 10), 
20 weeks (5 half-lives) after the second IMP administration.
The following visits will be site visits: 

Screening Visit 1

Screening Visit 2

Baseline Visit (Day 0/Visit 3) - randomization and IMP infusion

Last Visit of the Placebo-controlled Period, at the end of Week 4 (Visit 6 - second IMP 
infusion)
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 58 of 112

Completion Visit at Week 16 (Visit 9)

Safety Follow-Up Visit at Week 24 (Visit 10)

Withdrawal Visit (if applicable) - Patients who withdraw, except for those who withdraw 
their consent, will be asked to attend a Withdrawal Visit as soon as possible and a further 
Safety Follow-Up Visit (SFU), scheduled 20 weeks (5 half-lives) after the last IMP 
administration. 
All other study visits will be phone contact visits.
Patients will complete a daily eDiary from Screening Visit 2 until the Completion Visit
(Week 16/Visit 9)/Withdrawal Visit. Patients will be given an eDiary at Screening Visit 2 and 
must be trained in its use and compliance requirements. Patients will complete electronic 
cluster headache diary entries daily. At each clinic visit and phone contact, a compliance 
check of the eDiary data will be conducted by site staff. In addition to the eDiary compliance 
checks performed at the defined clinic visits and phone contacts, ongoing evaluation of 
eDiary compliance will be performed by the sites (based on eDiary reporting) and more 
frequent contact with patients may be needed in case of non-compliance.
If the date of a clinic visit or phone contact does not conform to the schedule, subsequent 
visits should be planned to maintain the visit schedule relative to the Baseline Visit
(Day 0/Visit 3). 
In exceptional situations, such as where COVID-19 pandemic restrictions impact the ability to 
perform site visits, site visits may only consist of blood sampling and urine sampling (for 
clinical laboratory tests, exploratory eptinezumab quantification, ADA including Nab, and 
exploratory biomarkers), ECG, vital signs, physical and neurological examinations, adverse 
event recording, and IMP administration, while the remaining assessments (eDiary, ePROs, 
C-SSRS, and investigator evaluations) can be conducted remotely via a virtual clinic visit.
These cases must be approved by the CRO’s medical monitor.
During the Placebo-controlled Period, ePROs which are scheduled in alignment with a clinic 
visit must be completed in the clinic; ePROs which are scheduled in alignment with a phone 
contact must be completed in the remote setting on the day the scheduled phone contact date. 
During the Active Treatment Period and Post-treatment Observational Period, ePROs which 
are scheduled in alignment with a clinic visit can be completed in the clinic or in the remote 
setting within 1 day prior to the scheduled clinic visit date. ePROs which are scheduled in 
alignment with a phone contact must be completed in the remote setting and can be completed 
on the day or within 1 day prior to the scheduled phone contact date. HCRU and 
WPAI:GH2.0 must be administered at site.
After completing or withdrawing from the study, the patient must be treated in accordance 
with usual clinical practice. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 59 of 112
8.2
Screening Visit 1
Signed informed consent must be in place before any study-related assessments are performed 
and may be obtained prior to Screening Visit 1.
Under exceptional circumstances, such as where COVID-19 pandemic restrictions impact the 
ability to perform site visits, the discussion with the patients about the Informed Consent 
Form(s) can be done as a virtual clinic visit and the Informed Consent Form(s) can be 
provided remotely in line with the US FDA and EMA guidances.43, 44According to the EMA 
guidance, this could comprise contacting the patients via phone or video-calls and obtaining 
oral consents, to be documented in the patients' medical records, supplemented with email 
confirmation. Any consent obtained this way should be documented and confirmed by way of 
normal consent procedures at the earliest opportunity when the patients are back at the clinical 
sites.44
The Screening Visit assessments may be extended over several days if needed. The date of the 
first assessment (except ICF) should be entered in the IRT system as the Visit Date.
For patients who enter the study already in cluster headache bout, Screening Visit 1 and 
Screening Visit 2 can be combined to capture all assessments for Screening Visit 1 and 
Screening Visit 2 on the same day.
The site staff should maintain monthly phone contact with the patient during Screening 
Period 1 to ensure the patient is prepared to schedule Screening Visit 2 as soon as possible 
after experiencing a CH bout. These contacts should be documented in the source 
documentation.
Prior to the Screening Visit 2, an eligibility review will be managed by the CRO and a 
confirmation that the patient can continue further with the study procedures is required before 
Screening Visit 2.
For patients with a known history of episodic cluster headache as defined by IHS ICHD-3 
classification,1 who meet all inclusion criteria and do not meet any of the exclusion criteria 
relevant for Screening Visit 1, and who do not enter in a cluster headache bout by the end of 
the Screening Period 1, Screening Period 1 can be extended by an additional 6 months. The 
extension is granted on a case-by-case basis by the CRO Medical Monitor, after a 
confirmation of eligibility, based on Screening Visit 1 data in the eCRF. 
Re-screening for Screening Visit 1 is allowed according to criteria outlined in 8.3.3.
For women of childbearing potential, the investigator must check current contraceptive 
methods. If relevant to do so, contraceptive therapy should be initiated if agreed by the patient 
and if there are no contraindications for the initiation of contraception.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 60 of 112
8.3
Screening Visit 2
After Screening Visit 2 and prior to Baseline Visit (Day 0/Visit 3), an additional eligibility 
review managed will be by the CRO and confirmation that the patient can continue further 
with the study procedures is required before randomization.
In exceptional cases, the visit interval between Screening Visit 2 and the Baseline Visit
(Day 0/Visit 3) may be extended with approval from the CRO Medical Monitor provided the 
CRO Medical Monitor accepts the rationale provided for the extension.
If a patient has insufficient number of attacks during Screening Period 2 to meet inclusion 
criterion 11, Screening Period 2 may be extended for an additional 7 days. See section 8.3.5
for further details.
Re-screening for Screening Visit 2 is allowed according to criteria outlined in 8.3.4.
At Screening Visit 2, the patient must be assisted with the provisioning and training of the 
eDiary and ePROs. Details will be provided in a separate user manual. See section 9.2.1.2 for 
further details on eDiary.
8.3.1
Pre-screening
Each site must record in a log which patients have been contacted and considered to attend 
Screening Visit 1.
8.3.2
Patient Identification Card
Each patient will be provided with a patient identification card that states, at a minimum, the 
name of the IMP, the study number, the patient identification number, the investigator’s 
name, and an emergency telephone number providing 24-hour service.
The patient identification card should be returned to the investigator upon completion of the 
patient’s participation in the study.
8.3.3
Re-Screening Visit 1
The Re-Screening Visit 1 must be conducted as a visit to the site. Re-screening of Screening 
Visit 1 is only allowed for patients with a Screening Visit 1 and who fail to meet one or more 
of the following selection criteria:
1.
If a patient with a confirmed diagnosis of eCH as defined by IHS ICHD-3 classification1
does not enter into a cluster headache bout during the maximum duration of Screening 
Period 1, including the potential 6-month extension of this period, granted by the CRO 
Medical Monitor. Refer to section 8.2.
2.
If the diagnosis of eCH as defined by IHS ICHD-3 classification1 cannot be confirmed 
due to disease duration of less than 12 months at the time of Screening Visit 1 (Inclusion 
criterion N°7). 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 61 of 112
3.
If a female patient with a confirmed diagnosis of eCH as defined by IHS ICHD-3 
classification becomes pregnant or is breastfeeding during Screening Period 1, the patient 
can repeat Screening Visit 1, if the study is still enrolling patients.
4.
If a patient with a confirmed diagnosis of eCH as defined by IHS ICHD-3 classification1
has been screen-failed on the amended eligibility criteria (Inclusion criteria 7 and 8 and 
Exclusion criterion 17). Re-screening of patients who have been previously screen-failed 
due the use of cannabinoids (either anamnesis or finding at Urine drug screen) must be 
approved by the CRO Medical Monitor, based on a confirmation from the investigator 
that the patient does not meet Exclusion criteria 10, 24 and 25.
At the new Screening Visit 1, the patient must sign new Informed Consent Form(s). At the 
new Screening Visit 1, the patient will be assigned a new screening number. A patient re-
screened for Screening Visit 1 must have a complete new Screening Visit 1, and all the 
eligibility criteria, relevant for Screening Visit 1 must be re-assessed at the new Screening 
Visit 1. 
Authorization for re-screening of Screening Visit 1 may only be granted by CRO Medical 
Monitor after a thorough review of all data from the original Screening Visit 1.
The following information will also be recorded in the eCRF at the new Screening Visit 1:

that the patient has previously been screened (Screening Visit 1) for the study

that re-screening has been authorized by the CRO Medical Monitor

the screening number that was assigned to the patient at the original Screening Visit 1
If a patient is re-screened, no data from the original Screening Visit 1 will be used.
A patient may only repeat Screening Visit 1 once.
8.3.4
Re-screening Visit 2
The Re-screening Visit 2 must be conducted as a visit to the site. Re-screening of Screening 
Visit 2 is only allowed for patients who fail to meet one or more of the following selection 
criteria:
1.
If a patient with a previously documented history of cluster headache bout duration of at 
least 6 weeks enters, for any reason, Screening Period 2 too late and/or the investigator 
considers that there is a risk that the patient will have a spontaneous remission in less 
than 6 weeks after screening (Inclusion criterion N°10).
2.
If a patient with a previously documented history of cluster headache bout duration of at 
least 6 weeks does not fulfil the required frequency of attacks (minimum of at least 7 total 
cluster headache attacks out of the 7-day Screening Period 2, including the extended 
Screening Period 2), the patient may be re-screened at the next bout.
3.
If the patient does not fulfil Exclusion criterion N°17 (Disallowed medications or 
medications allowed with restrictions), refer to Appendix II:
The required duration of a washout period for a medication that is disallowed prior to 
screening, or, 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 62 of 112
A stable usage period for a medication that is allowed with restrictions prior to 
screening.
The patient must already have either started the washout prior to screening or be on the 
allowed dosage as part of their standard clinical care. Washout or change in dosage may 
not be done specifically for inclusion into this study, but only if clinically indicated.
4.
A patient has answered “yes” to either Question 4 or Question 5 on the “Suicidal 
Ideation” portion of the C–SSRS or answered “yes” to any of the suicide-related 
behaviors (Exclusion criterion N°23). Refer to Section 9.6.7. These screen-fail patients 
may be considered for re-screen if the following conditions are met:
The patient was referred to an appropriate mental health professional and received 
treatment.
At least 6 months has elapsed since the screen-fail.
The patient has not answered yes to either Question 4 or Question 5 on the "Suicidal 
Ideation" portion of the C-SSRS, or answered "yes" to any of the suicide-related 
behaviors within the past 6 months, and are not considered by the investigator to be at 
significant risk for suicide.
5.
Patients with uncontrolled high blood pressure at Screening Visit 2 (Exclusion criteria 
N°14 and 18): may be considered for re-screen once their blood pressure is controlled in 
the opinion of the investigator; any use of antihypertensive medication and dose must be 
stable for at least 2 months prior to Re-Screening Visit 2
6.
Patients with a body mass index (BMI) ≥39 kg/m2 (Exclusion criterion N°19).
7.
For patients affected by COVID-19, e.g. being in quarantine with a positive COVID-19 
test with or without symptoms or other reasons related to COVID-19 which impacts the 
patients study participation, there will be an option of re-screening upon approval from 
the CRO MM.
Patients are not expected to have completed the full Screening Visit 2.
At the new Screening Visit 2, the patient must re-sign the Informed Consent Form(s). The 
patient will use the screening number assigned at Screening Visit 1.
The following information will also be recorded in the eCRF at the new Screening Visit 2:

that the patient has previously been screened (Screening Visit 2) for the study

that re-screening has been authorized by the CRO Medical Monitor
Authorization for re-screening may only be granted by the CRO Medical Monitor after a 
thorough review of all available data from the original Screening Visit 2.
A patient may only repeat Screening Visit 2 once.
8.3.5
Extension of Screening Period 2
If the patient with a confirmed diagnosis of eCH as defined by IHS ICHD-3 classification1, in 
a headache bout, does not meet the protocol requirement for minimum cluster headache 
activity (Inclusion criterion N°13) during Screening Period 2, based on the prospectively 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 63 of 112
collected data via the eDiary, Screening Period 2 may be extended for an additional 7 days. In 
these cases, the additional 7 days will begin on day 8. If the patient meets the required cluster 
headache activity by day 14 and the compliance requirements (6 out of 7 days compliance 
during days 8-14), the patient will continue in the study and the data from days 8-14 will be 
considered baseline data.
This is justified because the patient’s cluster activity may escalate slowly resulting in an 
insufficient number of attacks during the first 7 days following the first cluster headache 
attack.
If the patient does not fulfil Exclusion criterion N°17 (Disallowed medications or medications 
allowed with restrictions, refer to Appendix II) and the investigator considers that the criterion 
can be met by allowing up to 7 additional days in the Screening Period 2 for washout. The 
possibility to enroll this patient in the study will be discussed with the investigator and the 
decision will be taken in the context of known history of typical duration of the bout for the 
individual patient.
Extension of Screening Period 2 with additional 7 days can be requested for other reasons 
(e.g. additional exams, consultations etc.).
Request for extension of the Screening Period 2 must be immediately notified and discussed 
with the CRO’s medical monitor after a thorough review of all data from the Screening 
Visit 1 and 2.
8.4
Baseline Visit + IMP (Day 0/Visit 3)
The Baseline Visit (Day 0/Visit 3) also includes IMP administration and will occur 7 days 
after the Screening Visit 2. Inclusion and exclusion criteria review must be done prior to 
dosing at the Baseline Visit (Day 0/Visit 3). 
Prior to the Baseline Visit (Day 0/Visit 3), study-specific eligibility must be reviewed by the 
CRO. A confirmation from the CRO Medical Monitor that the patient can continue further 
with the study procedures is required before randomization.
For procedures preceding and following IMP administration, see section 8.6.
8.5
Visit 6 + IMP 
All patients will continue in the Active Treatment Period of the study and will receive at the 
end of Week 4 (Visit 6) a second IMP infusion as follows: 

Placebo - for patients who had received a first infusion with eptinezumab 400 mg at the 
Baseline Visit (Day 0/Visit 3)

Eptinezumab 400 mg - for patients who had received a first infusion with Placebo at the 
Baseline Visit (Day 0/Visit 3)
For procedures preceding and following IMP administration, see section 8.6.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 64 of 112
8.6
IMP Visits (Visits 3 and 6)
At IMP Visits, the patients will receive an IMP infusion. See section 6.1 and Infusion 
Guidelines for further instructions on procedures associated with administering the 
intravenous IMP.
Assessments involving interviews and scales must be administered at site before the infusion. 
ePROs will be completed in the clinic the following order; PGIC, SIS, EQ-5D-5L, HCRU, 
WPAI:GH2.0. 
The eDiary and electronic patient-reported outcomes (ePROs) must be completed prior to 
infusion. A compliance check of eDiary data will be conducted by site staff and the patient 
must be assisted with re-training if necessary. In addition to the eDiary compliance checks 
performed at defined clinic visits and phone contacts, ongoing evaluation of eDiary 
compliance will be performed by the site (based on eDiary reporting) and more frequent 
contact with the patients may be needed in case of non-compliance. See section 9.2.1.2 for 
further details on eDiary.
Prior to IMP infusion:

Patients must complete the ePROs. ePROs must be completed before pre-infusion blood 
sampling and urine sampling.

The following assessments must be conducted: vital signs including body temperature, 
concomitant medications, AEs, physical and neurological examination (if done at the 
discretion of the investigator), ECG, blood sampling and urine sampling and C-SSRS 
administration. 

Vital signs must be assessed prior to blood sampling.
During IMP infusion: Infusion-related reactions (IRRs must be checked as part of the overall 
AE collection. IRRs must be assessed after the AE collection. 
After end-of-IMP-infusion and before the patient is discharged from the site:

Patients must be monitored for at least 1 hour.

The following assessments must be conducted: vital signs including body temperature, 
IRRs and AEs. IRRs must be assessed after the AE collection. Vital signs must be assessed 
prior to blood sampling.

A blood sample for eptinezumab quantification and exploratory biomarkers must be taken 
within approximately 1 hour after end-of-infusion. 
Patients will be requested to stay longer should the investigator or designee determine this is 
clinically warranted. After the infusion, the patients will be under observation, but not 
confined to bed, unless the investigator decides, based on the patient’s condition, that it is in 
the best interest of the patient to be confined to bed.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 65 of 112
8.7
Phone Contacts (Visits 4, 5, 7, 8) 
The patient will be contacted via phone for eDiary compliance checks to ensure that selected 
assessments have been completed and for collection of relevant information such as AEs and 
concomitant medication and C-SSRS (Week 8/Visit 7 only), which must be administered by 
the authorized rater at the site.
A compliance check of eDiary data will be conducted by site staff and the patient must be 
assisted with re-training if necessary. In addition to the eDiary compliance checks performed 
at the defined clinic visits and phone contacts, ongoing evaluation of eDiary compliance will 
be performed by the site (based on eDiary reporting) and more frequent contact with patients 
may be needed in the case of non-compliance. See section 9.2.1.2 for further details on 
eDiary. 
Additionally, the following ePROs must be completed in the remote setting in alignment with 
the scheduled phone contacts (see Panel 2): PGIC (Visit 4, 5 and 7), SIS (Visit 5), EQ-5D-5L 
(Visit 5 and 7). During the Placebo-controlled Period, ePROs which are scheduled in 
alignment with a phone contact must be completed in the remote setting on the day the 
scheduled phone contact date. During the Active Treatment Period, ePROs which are 
scheduled in alignment with a phone contact must be completed in the remote setting and can 
be completed on the day or within 1 day prior to the scheduled phone contact date. 
Only site staff trained and listed in the delegation log will conduct phone contacts and hence 
be allowed to call the patient. Each phone contact must be documented in medical notes and 
used for source data verification when completing the eCRF and for subsequent monitoring.
Phone contacts should be planned to maintain the visit schedule relative to the Baseline Visit
(Day 0/Visit 3).
8.8
Completion Visit (Visit 9)
At the Completion Visit, the patient must be assisted with the closeout of the eDiary.
8.9
Withdrawal Visit
Patients who withdraw from the study prior to the Completion Visit (Week 16/Visit 9) will be 
asked to attend a Withdrawal Visit, if at all possible. The visit must be scheduled as soon as 
possible after withdrawal.
No new information will be collected from patients who withdraw from the study, except 
information collected in relation to the scheduled Withdrawal Visit and Safety Follow-Up 
Visit or needed for the follow-up of adverse events (section 10.5).
The reason for withdrawal must be recorded in the eCRF.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 66 of 112
For a patient who withdraws consent:

if the patient withdraws consent during a visit and then agrees to it being the final visit, the 
investigator will complete the visit as a Withdrawal Visit and all the data collected up to 
and including that visit will be used

if the patient withdraws consent during a telephone conversation, the investigator will ask 
the patient if he or she will attend a Withdrawal Visit. If the patient:
agrees to attend a Withdrawal Visit, all the data collected up to and including that visit 
will be used
refuses to attend a Withdrawal Visit, the investigator should attempt to follow the 
patient’s safety and future treatment; any information collected will only be recorded in 
the patient’s medical records

if the patient explicitly requests that the patient’s data collected from the time of 
withdrawal of consent onwards not be used, this will be respected
8.10
Safety Follow-up Visit (Visit 10)
The Safety Follow-Up Visit must be conducted as a visit to the site. The Safety Follow-Up 
Visit (SFU), should be scheduled 20 weeks (5 half-lives) after the last IMP administration.
A safety follow-up is conducted to capture adverse events that occur after the 
Completion/Withdrawal visit, as well as to follow up on the outcome of adverse events 
ongoing at the Completion/Withdrawal Visit.
Patients who withdraw from the study, except for those who withdraw their consent, will be 
asked to attend a Withdrawal Visit as soon as possible and a further Safety Follow-Up Visit at 
20 weeks (5 half-lives) after the last administration of IMP. 
For adverse events that were ongoing at the Completion/Withdrawal Visit and that resolved 
during the Safety Follow-up Period, the stop date must be recorded. For non-serious adverse 
events still ongoing at the safety follow-up, the Ongoing Adverse Event checkbox on the 
Adverse Event Form must be ticked. SAEs must be followed until resolution or the outcome 
is known.
The safety follow-up for patients who withdraw consent must be performed, if at all possible; 
any information collected will be recorded in the patients’ medical records.
8.11
Unscheduled Visit
Unscheduled visits can be completed if required as either site visit or telephone visits. At 
these visits, clinical safety laboratory tests, ECG, vital signs, physical examination, 
neurological examination, C-SSRS, body measurement, mental health consultation 
information or pregnancy tests can be performed. In case of any additional tests performed not 
covered by the existing tests specified in the protocol and the eCRF, the results can be 
reported in connection with an AE reporting (see section 10) or documented in the medical 
records, as applicable.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 67 of 112
8.12
End-of-study Definition
The end of the study for an individual patient is defined as the last protocol-specified contact 
with that patient. The overall end of the study is defined as the last protocol-specified contact 
with the last patient ongoing in the study.
9
Assessments
9.1
Screening and Baseline Procedures and Assessments
9.1.1
Demographics and Baseline Characteristics
Prior to enrolling a patient in the study, the investigator must ascertain that the patient meets 
the selection criteria. Refer to section 5.3.
The following assessments will be performed after the Informed Consent Form(s) have been 
signed at Screening Visit 1:

Demographics (age, sex, race). Race will not be collected if restricted per local regulations.

Prior episodic cluster headache documented history for review and documentation of 
previous treatment for episodic cluster headache within 12 months prior to Screening 
Visit 1 (see section 12 for definition of adequately documented records)

Other recent medication 

Relevant history (social, medical, psychiatric, neurological)

Substance use (e.g., smoking and alcohol consumption)

Height 

Family history of cluster headache

Urine Pregnancy test

Vital signs (including body temperature), weight
The following assessments will be performed Screening Visit 2:

Re-sign Informed Consent Form(s) signed at the Screening Visit 1

Prior episodic cluster headache documented history for review and documentation of 
previous treatment for episodic cluster headache within 12 months prior to Screening 
Visit 1 (see section 12 for definition of adequately documented records)

Other recent medication 

Relevant history (social, medical, psychiatric, neurological)

Substance use (e.g., smoking and alcohol consumption)

Signs and symptoms present at Screening Visit 2 and/or baseline (before IMP 
administration)

Serum Pregnancy test

Blood and urine samples for clinical safety laboratory tests

Urine drug screen

Vital signs (including body temperature), weight, ECGs
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 68 of 112

Examinations (physical, neurological)

C-SSRS

eDiary/ePRO training

eDiary recording
9.1.2
Diagnostic Assessments
IHS ICHD-3 guidelines1 sections 3.1 and 3.1.1 for episodic cluster headache are the 
diagnostic criteria to be used when assessing patient eligibility. Fulfilment of criteria for 
episodic cluster headache according to the inclusion criteria in this protocol will be confirmed 
via prospectively collected information in the eDiary during Screening Period 2 (i.e.,
minimum 7 and maximum of 56 CH attacks for the 7-day Screening Period 2). The lower and 
the upper limit for CH attack frequency is in line with the IHS ICHD-3 criteria for CH.
Definition of an eDiary Compliant Day: A Compliant Day is defined as any day where
either:

a headache event is reported

or evening diary is completed confirming patient did not have any new headache to report
Prior to enrolment, the investigator will review the data in the eDiary Eligibility Report to 
determine if eligibility criteria are fulfilled.
Panel 5
IHS ICHD-3 guidelines1 for Episodic Cluster Headache
3.1 Cluster Headache
A.
At least five attacks fulfilling criteria B–D
B.
Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15–180 minutes (when 
untreated)
C.
Either or both of the following:
(1) at least one of the following symptoms or signs, ipsilateral to the headache:
a.
conjunctival injection and/or lacrimation
b.
nasal congestion and/or rhinorrhoea
c.
eyelid oedema
d.
forehead and facial sweating
e.
miosis and/or ptosis
(2) a sense of restlessness or agitation
D.
Occurring with a frequency between one every other day and eight per day
E.
Not better accounted for by another ICHD-3 diagnosis.
3.1.1 Episodic cluster headache
A.
Attacks fulfilling criteria for 3.1 Cluster headache and occurring in bouts (cluster periods)
B.
At least two cluster periods lasting from seven days to one year (when untreated) and separated by pain-
free remission periods of ≥3 months.
In episodic cluster headache, during the cluster periods (bouts), the attacks occur in series 
lasting for weeks or months. Cluster periods usually last between two weeks and three months 
and are separated by remission periods usually lasting months (at least three months) or 
years.1
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 69 of 112
9.1.3
Drug and Alcohol Screen
A urine drug screen will be performed at the central laboratory for Screening Visit 2 only. A 
positive result must be discussed with the CRO Medical Monitor and will be evaluated in the 
context of concomitant medication use and exclusion criterion 10.
9.2
Efficacy Assessments
Efficacy assessments include the eDiary to record daily cluster headache data and ePROs 
(PGIC, SIS). 
Patients will record eDiary cluster headache data on a daily basis from the Screening Visit 2
until the Completion Visit (Week 16/Visit 9).
Patients will complete the PGIC and SIS along with the pharmacoeconomic assessment 
ePROs (see section 9.3). The ePROs should preferably be completed in the following order; 
PGIC, SIS, EQ-5D-5L, HCRU, WPAI:GH2.0. It is preferable that the same order of 
assessments is used per patient and the scheduled time of the day for the assessments is as 
consistent as possible across all the study visits. 
ePROs will be completed in alignment with clinic visits and phone contacts (see Panel 2):

ePROs which are scheduled in alignment with a clinic visit: 
During the Placebo-controlled Period - must be completed in the clinic; 
During the Active Treatment Period and Post-treatment Observational Period can be 
completed in the clinic or in the remote setting within 1 day prior to the scheduled clinic 
visit date. On the day of the Baseline Visit (Day 0/Visit 3), patients must complete the 
ePROs prior to infusion. 

ePROs which are scheduled in alignment with a phone contact: 
During the Placebo-controlled Period - must be completed in the remote setting on the 
day of the scheduled phone contact date; 
During the Active Treatment Period and Post-treatment Observational Period must be 
completed in the remote setting and can be completed on the day or within 1 day prior 
to the scheduled phone contact date.

HCRU and WPAI:GH2.0 must be administered at the site.
9.2.1
Clinical Outcome Assessments (COAs)
9.2.1.1
Use of COA Tools
The COA tools are the eDiary and ePROs, guidance to patients on how to complete the tools 
will be given by designated staff (see section 9.2.1.6). Detailed instructions will be provided 
in a separate eDiary and ePRO Training Module.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 70 of 112
The COA tools will be administered in the local language. Only those provided by Lundbeck 
that have been validated in the language to which they have been translated will be used in 
this study. 
The following COA tools will be used for efficacy assessments:

eDiary – to assess the number of daily cluster headache attacks, pain severity and 
medication use (i.e., the start and stop dates of cluster headache attacks, and use of acute 
eCH medications).

PGIC - to assess overall change in the severity of illness following treatment.

SIS – to assess quality of life resulting from insomnia as caused by cluster headache 
attacks
9.2.1.2
eDiary
At Screening Visit 2, the patient must be assisted with the provisioning of the eDiary and 
must be trained in eDiary use and compliance requirements by designated site staff. Patients 
will be instructed to complete the eDiary on a daily basis, from Screening Visit 2 until the
Completion Visit (Week 16/Visit 9). During the Completion Visit (Week 16/Visit 9) or the 
Withdrawal Visit (for patients who withdraw), eDiary close-out must be performed while the 
patient is on site. Details will be provided in a separate eDiary Training Module.
The content of the cluster headache diary is developed on key characteristics as mentioned in 
the definition of episodic cluster headache (see section 9.1.2). The eDiary consists of 
applications and reports which will be used to derive the cluster headache endpoints. For each 
day, the patient should record if they experienced any cluster headache attacks. For each 
experienced cluster headache attack, the start date and time will be collected. The patient will 
record further daily information regarding cluster headache characteristics and intake of 
cluster headache acute medication. Cluster headache items will be assessed with a yes/no 
response; and severity will be rated on an ordinal scale ranging from 0-4 (headache pain 
ratings: 0=none/barely any pain; 1=mild; 2= moderate; 3= severe; 4=excruciating).46
Additional details regarding the questions that patients will answer can be found in the eDiary 
Training Module.
Screening Visit 2 will correspond to the day of eDiary distribution and will start the 7-day 
eDiary Screening Period 2. Any patient found to be ineligible for the study during Screening 
Period 2 will not be randomized. An eDiary Eligibility Report will be used to review baseline
cluster headache attack days and eDiary compliance during the 7-day Screening Period 2 for 
the eligibility assessment of:

a minimum of at least 7 total cluster headache attacks out of the 7-day period

a maximum of 56 cluster headache attacks out of the 7-day period

compliance by entry of cluster headache data for at least 6 out of the 7 days of Screening 
Period 2
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 71 of 112
On the Baseline Visit (Day 0/Visit 3), patients must ensure to complete eDiary recording of 
cluster headache attacks that ended prior to infusion (i.e., for cluster headaches attacks which 
are ongoing or not yet recorded in the eDiary).
On each day during the study until the Completion Visit (Week 16/Visit 9)/Withdrawal Visit, 
the patient will be asked to record eDiary data for the day. 
Clinical study site staff will be given access to the eDiary data. Compliance data (based on 
eDiary reporting) will be made available throughout the study to site staff for review on a 
regular basis. At least 6 out of 7 days per week compliance is needed during Screening 
Period 2. At each clinic visit and phone contact, a compliance check of eDiary will be
conducted by site staff. Additionally, ongoing evaluation of eDiary compliance will be 
performed by the site and more frequent contact with patients may be needed in case of non-
compliance. All follow-up with patients regarding eDiary compliance should be documented 
in the source records.
9.2.1.3
Patient Global Impression of Change (PGIC)
The PGIC is a single patient-reported item reflecting the patient’s impression of change in 
their disease status since the Baseline Visit (Day 0/Visit 3) (that is, in relation to activity 
limitations, symptoms, emotions, and overall quality of life). The item is rated on a 7-point 
scale, where a high score indicate improvement (very much improved; much improved; 
minimally improved; no change; minimally worse; much worse; very much worse). It takes 
approximate 1 minute to complete the scale.
9.2.1.4
Sleep Impact Scale (SIS)
The SIS47 is a patient-reported scale to assess quality of life resulting from sleep disturbance. 
The SIS questionnaire includes 35 items belonging to 7 domains to assess sleep impact: daily 
activities (5 items); emotional well-being (4 items); emotional impact (4 items); 
energy/fatigue (5 items); social well-being (6 items); mental fatigue (3 items); and satisfaction 
with sleep (8 items). Each item, for 6 out of the 7 domains, is rated on a 5-point scale ranging 
from 1 (“always” or “all of the time”) to 5 (“never” or “none of the time”), whereas 
satisfaction with sleep is rated on a 5-point scale ranging from 1 (very satisfied) to 5 (very 
dissatisfied). Each domain yields a score ranging from 0-100. A higher score indicated better 
quality of life (reverse scoring for the satisfaction with sleep domain). It takes approximately 
10 minutes to complete the SIS.
9.2.1.5
External COA Monitoring Oversight
Lundbeck reserves the right to use external quality oversight to ensure eDiary compliance and 
data quality, as well as ensure accurate completion of COAs. For this study, the CRO will 
conduct the external data monitoring (to be agreed with Lundbeck).
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 72 of 112
9.2.1.6
COA Tool Training
The COA tools are patient-reported. Therefore, designated site staff will receive guidance on 
good standards in completion of the COAs, in order to adequately train patients on 
completion of the eDiary and ePROs. 
COA training will be conducted by the CRO (as agreed with Lundbeck). Site staff will 
complete their designated training curriculum based on their initial qualification status and 
assigned role. Any exceptions must be discussed and approved by Lundbeck and/or its 
designee. The training program will also include general COA quality assurance and 
management guidance.
Only site staff who have adequate experience with cluster headache and who have received 
adequate training on good standards in completion of the eDiary and ePROs will be 
authorized to train the patients on completion of the eDiary and ePROs in the study. 
Documentation of training will be provided to site staff for archiving in the investigator trial 
master file (TMF). 
New eDiary and ePRO trainers joining the study must be trained similarly.
9.3
Pharmacoeconomic Assessments
Pharmacoeconomic assessments include ePROs (EQ-5D-5L, HCRU, WPAI:GH2.0). 
Patients will complete these ePROs along with the efficacy assessment ePROs (PGIC and 
SIS, see sections 9.2.1.3 and 9.2.1.4). The ePROs should preferably be completed in the 
following order; EQ-5D-5L, HCRU, WPAI:GH2.0). It is preferable that the same order of 
assessments is used per patient and the scheduled time of the day for the assessments is as 
consistent as possible across all the study visits.
ePROs will be completed in alignment with clinic visits and phone contacts:

ePROs which are scheduled in alignment with a clinic visit (see Panel 2): 
During the Placebo-controlled Period - must be completed in the clinic; 
During the Active Treatment Period and Post-treatment Observational Period can be 
completed in the clinic or in the remote setting within 1 day prior to the scheduled clinic 
visit date. On the day of the Baseline Visit (Day 0/Visit 3), patients must complete the 
ePROs prior to infusion. 

ePROs which are scheduled in alignment with a phone contact (see Panel 2):
During the Placebo-controlled Period - must be completed in the remote setting on the 
day of the scheduled phone contact date; 
During the Active Treatment Period and Post-treatment Observational Period must be 
completed in the remote setting and can be completed on the day or within 1 day prior 
to the scheduled phone contact date.

HCRU and WPAI:GH2.0 must be administered at the site.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 73 of 112
9.3.1
Clinical Outcome Assessments (COAs)
9.3.1.1
Use of COA Tools
Refer to section 9.2.1.1 for further information on use of COA tools. 
The following COA tools will be used for pharmacoeconomic assessments:

EQ-5D-5L - to assess the overall state of health 

HCRU - to assess cluster headache-specific healthcare resource utilization 

WPAI:GH2.0 - to assess overall effect of health on productivity at work and daily activities
9.3.1.2
Euroqol 5 Dimension – 5 Levels (EQ-5D-5L)
The EQ-5D-5L48 is a patient-reported assessment designed to measure the patient’s wellbeing. 
It consists of 5 descriptive items (mobility, self-care, usual activities, pain/discomfort, and 
depression/anxiety) and a visual analogue scale (VAS) of the overall health state. Each 
descriptive item is rated on a 5-point index ranging from 1 (no problems) to 5 (extreme 
problems) and a single summary index (from 0 to 1) can be calculated. The VAS ranges from 
0 (worst imaginable health state) to 100 (best imaginable health state). It takes approximately 
5 minutes to complete the EQ-5D-5L.
9.3.1.3
Health Care Resource Utilization (HCRU)
Cluster headache-specific healthcare resource utilization information will be collected in 
terms of outpatient health care professional visits, emergency room visits, hospital 
admissions, as well as duration of hospital stays during the past 4 weeks. Clinical site 
personnel and patients will be instructed to capture utilization that takes place outside of visits 
associated with their participation in the clinical trial.
9.3.1.4
Work Productivity and Activity Impairment: General Health version 2 
(WPAI:GH2.0)
The WPAI:GH2.049 is a patient self-rated scale designed to provide a quantitative measure of 
the work productivity and activity impairment due to a health condition. The WPAI:GH2.0 
assess activities over the preceding 7 days and consists of 6 items: 1 item assess employment 
(yes/no); 3 items assess the number of hours worked, the number of hours missed from work 
due to the patient’s condition, or due to other reasons; and 2 visual numerical scales to assess 
how much the patient’s condition affects their productivity at work and their ability to 
complete normal daily activities. It takes approximately 5 minutes to complete the 
WPAI:GH2.0.
9.3.1.5
External COA Monitoring Oversight
See section 9.2.1.5.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 74 of 112
9.3.1.6
COA Training
See section 9.2.1.6.
9.4
Pharmacokinetic Assessments
9.4.1
Blood sampling for eptinezumab quantification
The blood samples (maximum total volume: 12 mL per patient) for eptinezumab
quantification in plasma will be drawn in accordance with Panel 2. The samples will be 
analysed for free eptinezumab using a validated bioanalytical method by a bioanalytical 
laboratory under the responsibility of Sponsor. The bioanalytical method will be defined in a 
bioanalytical protocol and be reported in a bioanalytical report. 
The results will be reported separately.
9.5
Pharmacodynamic Assessments
9.5.1
Pharmacodynamic/Exploratory Biomarkers
Blood samples (maximum total volume 24 mL) for the pharmacodynamic/exploratory 
biomarker assessment of the CGRP and eptinezumab-CGRP complex will be collected in 
accordance with Panel 2. The blood sampling and handling procedures are described in the 
study-specific Laboratory Specification Manual.
The results from these analyses will be reported separately.
9.6
Safety Assessments
9.6.1
Adverse Events
The patients will be asked a non-leading question (for example, “How do you feel?”, “How 
have you felt since your last visit?”) at each visit, starting at Screening Visit 2. Adverse events 
(including worsening of concurrent disorders, new disorders, and pregnancies) either 
observed by the investigator or reported spontaneously by the patient will be recorded, and the 
investigator will assess the seriousness and the intensity of each adverse event and its 
relationship to the IMP. Results from relevant tests and examinations, such as clinical safety 
laboratory tests, vital signs, and ECGs, or their corresponding conditions will also be recorded 
as adverse events if considered by the investigator to be clinically significant.
See section 10 for further information on adverse events.
9.6.2
Clinical Safety Laboratory Tests
The clinical safety laboratory tests are listed in Panel 6.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 75 of 112
Panel 6
Clinical Safety Laboratory Tests
Haematology
Liverb
Immune response lab kith
B-haemoglobin [HGB]
B-erythrocyte count [RBC]
B-total leucocyte count [WBC]
B-neutrophilsa [NEUTLE]
B-eosinophilsa [EOSLE]
B-basophilsa [BASOLE]
B-lymphocytesa [LYMLE]
B-monocytesa [MONOLE]
B-thrombocyte count [PLAT]
B-haematocrit [HCT]
P-prothrombin time [PT]
S-total bilirubin [BILI]
S-conjugated bilirubin [BILDIR]
S-alkaline phosphatase [ALP]
S-alanine aminotransferase [ALT]
S-aspartate aminotransferase [AST]
S-gamma-glutamyl transferase [GGT]
P-histamine [HISTAMINE]
S-tryptase [TRYPTASE]
immunoglobulin E [IgE]
complement C3, C4 [C3 and 
C4]
Infectionc
S-C-reactive protein [CRP]
Electrolytesb
Kidneyb
Urineg
S-sodium [SODIUM]
S-potassium [K]
S-calcium (total) [CA]
S-creatinine [CREAT]
S-urea nitrogen [UREAN]
U-protein (dipstick) [PROT]
U-glucose (dipstick) [GLUC]
U-blood (dipstick) [OCCBLD]
Urine drug screen
Endocrine and Metabolicb
Lipidsb,d
Pregnancye
S-albumin [ALB]
S-glucosed [GLUC]
B-HbA1c [HBA1C]
S-creatine phosphokinase [CK]
S-low density lipoprotein [LDL]
S-high density lipoprotein [HDL]
S-triglycerides [TRIG]
S-cholesterol (total) [CHOL]
S-hCGf [HCG]
Urine (dipstick)
B = blood; P = plasma; S = serum; U = urine
a
Count and % of total leucocytes
b
Clinical chemistry
c
Performed at Screening Visit 2 only
d
Fasting, when possible
e
Only for women of childbearing potential
f
Performed at Screening Visit 2 and Safety Follow-Up Visit only
g
If urine dipstick is positive, a urine microscopic panel will be conducted
h
Performed per investigator judgement, see section 10.1.3
Blood samples for the clinical safety laboratory tests will be collected as outlined in Panel 2.
The blood sampling and handling procedures are described in the study-specific Laboratory 
Specification Manual.
It is mandatory for blood and urine samples to be analysed by the central laboratory. If 
necessary, for logistical reasons and per the investigator’s discretion, a local laboratory may 
also be used at Screening Visit 2. Central laboratory results supersede local laboratory results.
If central laboratory results are not available for the eligibility assessment, the local laboratory 
results may be used to confirm eligibility.
The investigator must review (initial and date) the results of the clinical safety laboratory tests 
as soon as possible after receipt of those results. Out-of-range values must be interpreted by 
the investigator as “not clinically significant” or “clinically significant” with a comment 
concerning the planned follow-up. Tests for clinically significant out-of-range values must be 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 76 of 112
repeated, or an appropriate clinical follow-up must be arranged by the investigator and 
documented on the laboratory report, until the value has stabilized or until the value has 
returned to a clinically acceptable value (regardless of relationship to the IMP). A patient with 
a value that is out-of-range at the Completion Visit (Week 16/Visit 9) or Withdrawal Visit 
and considered clinically significant must be followed in accordance with usual clinical 
practice. If the clinically significant out-of-range clinical safety laboratory test value has not 
normalized or stabilized or a diagnosis or a reasonable explanation has not been established 
by the Safety Follow-up Visit, the investigator must decide whether further follow-up visits 
are required (this may include an additional medical examination and/or additional blood 
sampling). Any out-of-range values followed after the last protocol-specified contact with the 
patient will be documented in the patient’s medical records.
Any out-of-range clinical safety laboratory test value considered clinically significant by the 
investigator must be recorded as an adverse event on an Adverse Event Form, starting from 
the time the patient has signed/re-signed the informed consent form(s) at Screening Visit 2.
The central laboratory will be notified by Lundbeck when the biological samples may be 
destroyed.
9.6.3
Vital Signs
The investigator may appoint a designee (for example, nurse or paramedic) to measure vital 
signs, provided this is permitted according to local regulations and provided the investigator 
has trained the designee how to measure vital signs. The investigator must take responsibility 
for reviewing the findings.
Pulse rate and blood pressure will be measured using a standard digital meter. Pulse rate and 
blood pressure will be measured in the following order: supine, sitting, and standing after the 
patient has rested in each position for at least 3 minutes.
At IMP visits, vital signs including body temperature is assessed both prior to and after 
infusion. When coinciding, vital signs including body temperature must be assessed prior to 
blood sampling.
Any out-of-range vital sign considered clinically significant by the investigator must be 
recorded as an adverse event on an Adverse Event Form, starting from the time the patient has 
signed/re-signed the informed consent form(s) at Screening Visit 2.
9.6.4
Height and Weight
The patient’s height will be measured once at Screening Visit 1.
The patients will be weighed wearing light clothing and no shoes. A similar amount of 
clothing must be worn on each occasion.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 77 of 112
Any weight change considered clinically significant by the investigator must be recorded as 
an adverse event on an Adverse Event Form, starting from the time the patient has signed/re-
signed the informed consent form(s) at Screening Visit 2.
9.6.5
Electrocardiograms (ECGs)
A standard 12-lead ECG will be recorded using digital ECG recording equipment provided to 
the investigator or, upon agreement, to an external cardiology centre. The ECGs will be 
transferred digitally to a central ECG laboratory for evaluation. The investigator will be 
provided with the results and a cardiological interpretation of the ECG from the central ECG 
laboratory.
The results from the central ECG laboratory will include the PR, QRS, QT, and QTc 
intervals.
The investigator has the final decision on the interpretation of the ECG results. Any abnormal 
ECG result or out-of-range ECG parameter value considered clinically significant by the 
investigator must be recorded as an adverse event on an Adverse Event Form, starting from 
the time the patient has signed/re-signed the informed consent form(s) at Screening Visit 2.
9.6.6
Physical and Neurological Examinations
Physical and Neurological examinations for all clinic visits (except Screening Visit 2 which is 
mandatory) are to be conducted at the discretion of the investigator. If these examinations are 
conducted at IMP infusion Visit, these must be performed prior to the infusion.
The investigator may appoint a designee to be primarily responsible for performing the 
physical and neurological examinations, such as physician assistant or nurse practitioner (as 
applicable) provided this is permitted according to local regulations. The investigator must 
take responsibility for reviewing the findings. Whenever possible, the same individual should 
perform all the physical examinations.
The physical examination must, at a minimum, include an examination of appearance, 
extremities, skin, head, neck, eyes, ears, nose, throat, lungs, chest, heart, abdomen (including 
the renal regions) and musculoskeletal system.
Any abnormal finding or out-of-range value considered clinically significant by the 
investigator must be recorded as an adverse event on an Adverse Event Form, starting from 
the time the patient has signed/re-signed the informed consent form(s) at Screening Visit 2.
9.6.7
Columbia-Suicide Severity Rating Scale
The C-SSRS is a semi-structured interview developed to systematically assess suicidal 
ideation and behaviour of patients participating in a clinical study.50 The C-SSRS has 
5 questions addressing suicidal ideation, 5 sub-questions assessing the intensity of ideation, 
and 4 questions addressing suicidal behaviour. For this study, the following versions of the 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 78 of 112
scale are used: the “Baseline/Screening” version (lifetime and 1-month assessment) and the 
“Since last visit” version (for all subsequent visits). It takes approximately 5 minutes to 
administer and rate the C-SSRS.
The C-SSRS must be administered in the local language. 
The C-SSRS should only be administered by a qualified rater. For each individual patient, the 
same certified rater should preferably rate the patient throughout the study. In case of 
unforeseen circumstances, certified back-up raters should be available throughout the study. 
Any exceptions must be discussed and approved by Lundbeck and/or its designee. 
Rater training and certification will be conducted by the CRO as agreed with Lundbeck. 
Raters will complete their designated training curriculum based on their initial qualification 
status and assigned role. Only raters who qualify on study specific Rater Certification 
Programme will be authorized to administer the C-SSRS in the study. Documentation of 
training and certification will be provided to raters for archiving in the investigator trial 
master file (TMF). No patient must be rated before the documentation has been archived. 
New raters joining the study must be trained and certified by using the same certification 
process. Detailed instructions on how to administer the C-SSRS will be provided to the site in 
a C-SSRS Guideline.
In case the C-SSRS assessment indicates elevated acute suicide risk (the patient answering: 
"yes" to suicidal ideation questions 4 or 5 or answering: "yes" to suicidal behaviour at any 
time during the study, it is the responsibility of the investigator to withdraw the patient from 
further treatment and to promptly refer the patient to an appropriate mental health care 
professional for a psychiatric evaluation. 
Any finding on the C-SSRS that is considered clinically significant by the investigator should 
be reported as an AE.
9.6.8
Anti-Drug Antibody (ADA) including Neutralizing Antibody (Nab) Assessments
Blood samples for ADA, including NAb assessments (maximum total volume 7.5 mL), will 
be collected in accordance with Panel 2. The samples will be analysed using validated 
methods by an analytical laboratory under the responsibility of Sponsor. The analytical 
methods will be defined in analytical protocols and be reported in analytical reports.
9.7
Biobanking
9.7.1
General Considerations
This study includes collection of blood samples for long term storage and use in a possible 
future explorative biomarker research study, that may help to increase our understanding of 
the aetiology of psychiatric or neurological diseases, such as migraine and the molecular basis 
of the drug response.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 79 of 112
Although the potential future exploratory biomarker analyses will help to increase our 
understanding of the aetiology of episodic cluster headache and the molecular basis of the 
drug response, the efforts described in this protocol are strictly research based. Therefore, as 
the complex interactions between genes, biomarkers and disease are currently not 
characterized to a level that translates to a meaningful clinical advantage, individual results 
from the exploratory biomarker analyses will as per usual not be given to either the study 
participants or the investigator. For the same reasons, individual results will not be added to 
the patients’ medical records.
The patients will have no direct benefit from the exploratory biomarker analyses.
To ensure privacy protection, the blood samples for RNA gene expression profiling, 
proteomics/metabolomics analysis and future ADA assessments will be single-coded using 
the patient’s screening number. The blood samples for the pharmacogenetic (DNA) biomarker 
analysis will be double-coded, i.e. one code key will be stored at the site and the other at 
Lundbeck. To link a DNA sample to a specific subject, both code keys are needed.
The blood samples collected for the possible future exploratory biomarker analysis may be 
shared with academic and public institutions and other companies. However, Lundbeck will 
retain full control of the samples and their use in accordance with the information in the 
Patient Information Sheet and a Material Transfer Agreement. Furthermore, the results based 
on the analysis of the samples may be pooled across studies to increase the statistical power of 
the analyses. 
9.7.2
Blood Sampling for Gene Expression Profiling
Blood samples for gene expression profiling will be collected in two PAXgene RNA tubes 
(2.5 mL) or equivalent in accordance with Panel 2. The maximum volume of blood to be 
collected during the study for this purpose will be 15 mL. 
Samples for gene expression profiling will be shipped to Lundbeck Biobank (at Azenta Life 
Sciences, Indianapolis, IN, USA) for storage. Sample preparation and analysis may be 
performed by CRO or by a bona fide research collaborator.
9.7.3
Blood Sampling for Metabolomics and/or Proteomics
Blood samples for plasma separation and metabolomics and/or proteomics will be collected in 
one 10 mL K2 EDTA tube or equivalent in accordance with Panel 2. The maximum volume 
of blood to be collected during the study for this purpose will be 30 mL. 
Samples for gene expression profiling will be shipped to Lundbeck Biobank (at Azenta Life 
Sciences, Indianapolis, IN, USA) for storage. Sample preparation and analysis may be 
performed by CRO or by a bona fide research collaborator.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 80 of 112
9.7.4
Blood Sampling for Pharmacogenetics
It is optional for the patient to donate a blood sample for exploratory pharmacogenetic 
analysis.
Blood samples for subsequent DNA extraction and aliquoting will be collected in 9 mL 
K3 EDTA tube or equivalent in accordance with Panel 2. The maximum volume of blood to 
be collected during the study for this purpose will be 9 mL.
The extracted DNA aliquots will be shipped to Lundbeck Biobank (at Azenta Life Sciences, 
Indianapolis, IN, USA) for storage. Sample preparation and analysis may be performed by 
CRO or by a bona fide research collaborator.
The genetic variants to be analysed may include single nucleotide polymorphisms (SNPs) and 
copy number variations (CNVs). The analytical methods may be polymerase chain reaction 
(PCR), quantitative PCR (qPCR), sequencing, or whole genome scans on microarrays.
9.7.5
Blood sampling for possible future anti-drug antibody assessments
Whole blood samples for serum separation and potential future anti-eptinezumab antibody 
analyses will be collected in 2.5 mL silica clot activator (SST) tube or equivalent in 
accordance with Panel 2.
The maximum volume of blood to be collected during the study for this purpose will be 
7.5 mL.
The samples for future anti-drug antibody assessments will be shipped to Lundbeck Biobank 
(at Azenta Life Sciences, Indianapolis, IN, USA) for storage. Sample preparation and analysis 
may be performed by CRO or by a bona fide research collaborator. 
9.7.6
Blood Sampling for Future Exploratory Biomarkers
Blood sample for plasma separation and explorative biomarkers assessment will be collected 
in one 4 mL K2 EDTA tube or equivalent in accordance with Panel 2.
The blood sampling and handling procedures are described in the Study Operations Manual. 
The maximum volume of blood to be collected during the study for this purpose will be 
20 mL. 
The plasma samples will be shipped to Lundbeck Biobank (at Azenta Life Sciences, 
Indianapolis, IN, USA) for storage. Sample preparation and analysis may be performed by 
CRO or by a bona fide research collaborator. The samples and any derived material will be 
destroyed ≤10 years after the end of the study (as defined in section 9.4).
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 81 of 112
9.8
Order of Assessments
At the Baseline Visit (Day 0/Visit 3), prior to IMP infusion:

After randomization, patients must complete the ePROs. ePROs must be completed before 
the pre-infusion blood sampling and urine sampling.

The following assessments must be conducted: vital signs including body temperature, 
concomitant medications, AEs, physical and neurological examination (if done at the 
discretion of the investigator), ECG, blood sampling and urine sampling and C-SSRS 
administration. 

Vital signs must be assessed prior to blood sampling.
At the Baseline Visit (Day 0/Visit 3), during IMP infusion: IRRs must be checked as part of 
the overall AE collection. IRRs must be assessed after the AE collection. 
At the Baseline Visit (Day 0/Visit 3), After end-of-IMP-infusion and before the patient is 
discharged from the site:

Patients must be monitored for at least 1 hour.

The following assessments must be conducted: vital signs including body temperature, 
IRRs and AEs. IRRs must be assessed after the AE collection. Vital signs must be assessed 
prior to blood sampling.

A blood sample for eptinezumab quantification and exploratory biomarkers must be taken 
within approximately 1 hour after end-of-infusion. 
ePROs:

ePROs which are scheduled in alignment with a clinic visit: 
During the Placebo-controlled Period - must be completed in the clinic; 
During the Active Treatment Period and Post-treatment Observational Period can be 
completed in the clinic or in the remote setting within 1 day prior to the scheduled clinic 
visit date. On the day of the Baseline Visit (Day 0/Visit 3), patients must complete the 
ePROs prior to infusion. 

ePROs which are scheduled in alignment with a phone contact: 
During the Placebo-controlled Period - must be completed in the remote setting on the 
day of the scheduled phone contact date; 
During the Active Treatment Period and Post-treatment Observational Period must be 
completed in the remote setting and can be completed on the day or within 1 day prior 
to the scheduled phone contact date.

HCRU and WPAI:GH2.0 must be administered at the site.

ePROs should preferably be completed in the following order; PGIC, SIS, EQ-5D-5L, 
HCRU, WPAI:GH2.0. It is preferable that the same order of assessments is used per 
patient and the scheduled time of the day for the assessments is as consistent as possible 
across all the study visits. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 82 of 112
9.9
Total Volume of Blood Drawn and Destruction of Biological Material
The total volume of blood drawn from each patient will be approximately 200 mL during the 
study.
Additional blood samples may be required if the original blood samples are not viable or if re-
testing is required.
The biobank blood samples and any derived material for potential future exploratory gene 
expression profiling, metabolic or proteomic biomarker analyses or anti-drug antibody 
assessments will be destroyed ≤10 years after the end of the study (see definition in 
section 8.11).
The biobank blood samples and any derived material for potential future exploratory 
pharmacogenetic analyses will be destroyed ≤15 years after the end of the study (see 
definition in section 8.11).
Samples for eptinezumab quantification, exploratory biomarkers and anti-drug antibody 
assessments will be retained for up to 5 years after reporting of the study (see section 17.2).
9.10
Treatment Compliance
Responsible study personnel will administer the infusions of IMP. Treatment compliance 
verification should be documented in the patient’s source documents and study specific IMP 
documents and verified by a CRA during monitoring. 
Anyone administering the IMP to the patient must be listed in the delegation log. 
The information from the IMP Administration Form must be entered in the eCRF.
10 Adverse Events
10.1
Definitions
10.1.1
Adverse Event Definitions51
Adverse event – is any untoward medical occurrence in a patient or clinical study patient 
administered a medicinal product and which does not necessarily have a causal relationship 
with this treatment.
An adverse event can therefore be any unfavourable and unintended sign (including clinically 
significant out-of-range values from relevant tests, such as clinical safety laboratory tests, 
vital signs, ECGs), symptom, or disease temporally associated with the use of a medicinal 
product, regardless of whether it is considered related to the medicinal product.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 83 of 112
A worsening of a pre-existing or chronic condition is considered an adverse event and must be 
reported as such. Medical conditions, which existed prior to the time of informed consent into 
the clinical study are part of the patient's medical history and are not considered an adverse 
event. Unchanged, chronic, non-worsening or pre-existing conditions from the time of 
informed consent are not adverse events and should not be reported as such. 
Adverse events (serious and non-serious) must be collected, recorded, and reported to 
Lundbeck from the time the patient has signed/re-signed the informed consent form(s) at 
Screening Visit 2. Any event (serious or non-serious) that are reported to the investigator prior 
to Screening Visit 2 should be considered and recorded as medical history.
Serious adverse event (SAE) – is any adverse event that:

results in death

is life-threatening (this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
had it been more severe)

requires inpatient hospitalization or prolongation of existing hospitalization

results in persistent or significant disability/incapacity

is a congenital anomaly/birth defect

is medically important (this refers to an event that may not be immediately life-threatening 
or result in death or hospitalization, but may jeopardize the patient or may require 
intervention to prevent any of the SAEs defined above)
Examples of medically important events are intensive treatment for allergic bronchospasm; 
blood dyscrasia or convulsions that do not result in hospitalization; or development of drug 
dependency or drug abuse.
Planned hospitalizations or surgical interventions for a condition that existed before the 
patient signed the Informed Consent Form and that did not change in intensity are not adverse 
events. Emergency room visits that do not result in admission to the hospital are not 
necessarily SAEs; however, they must be evaluated to determine whether they meet any of the 
SAE definitions (for example, life-threatening or other serious [medically important] event).
Non-serious adverse event – is any adverse event that does not meet the definition of an SAE.
If there is any doubt as to whether an adverse event meets the definition of an SAE, a 
conservative viewpoint must be taken, and the adverse event must be reported as an SAE.
Suspected unexpected serious adverse reaction (SUSAR) – is any adverse event that is 
assessed as serious, unexpected (its nature or intensity is not consistent with the current 
version of the Investigator’s Brochure,24 and related to a medicinal product by either the 
investigator or Lundbeck.
Overdose – is a dose administered to the patient that exceeds the dose prescribed to that 
patient. Any overdose (and associated symptoms) must, at a minimum, be recorded as a non-
serious adverse event.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 84 of 112
10.1.2
Adverse Event Assessment Definitions
Assessment of Intensity
The investigator must assess the intensity of the adverse event using the following definitions, 
and record it on the Adverse Event Form:

Mild – the adverse event causes minimal discomfort and does not interfere in a significant 
manner with the patient’s normal activities.

Moderate – the adverse event is sufficiently uncomfortable to produce some impairment of 
the patient’s normal activities.

Severe – the adverse event is incapacitating, preventing the patient from participating in the 
patient’s normal activities.
Assessment of Causal Relationship
The investigator must assess the causal relationship between the adverse event and the IMP 
using the following definitions, and record it on the Adverse Event Form and the Serious 
Adverse Event Form (if applicable):

Probable – the adverse event has a strong temporal relationship to the IMP or recurs on re-
challenge, and another aetiology is unlikely or significantly less likely.

Possible – the adverse event has a suggestive temporal relationship to the IMP, and an 
alternative aetiology is equally or less likely.

Not related – the adverse event has no temporal relationship to the IMP or is due to 
underlying/concurrent disorder or effect of another drug (that is, there is no causal 
relationship between the IMP and the adverse event).
An adverse event is considered causally related to the use of the IMP when the causality 
assessment is probable or possible. 
For pre-treatment adverse events, a causality assessment is not relevant.
Assessment of Outcome
The investigator must assess the outcome of the adverse event using the following definitions, 
and record it on the Adverse Event Form and the Serious Adverse Event Form (if applicable):

Recovered – the patient has recovered completely, and no symptoms remain.

Recovering – the patient’s condition is improving, but symptoms still remain.

Recovered with sequelae – the patient has recovered, but some symptoms remain (for 
example, the patient had a stroke and is functioning normally, but has some motor 
impairment).

Not recovered – the patient’s condition has not improved and the symptoms are unchanged 
(for example, an atrial fibrillation has become chronic).

Death
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 85 of 112
10.1.3
Management of Reactions to Study Drug
There are no specific antidotes to an infusion of eptinezumab. 
A medical emergency should be treated appropriately by the investigator using proper 
standard of care, according to their typical clinical practice and local guidelines for that 
emergency condition.
Should a medical condition arise that the investigator believes is related to the study drug, 
clinical judgment should be used to provide the appropriate response including the 
consideration of discontinuation of study drug. If a patient experiences an anaphylactic 
reaction or another severe and/or serious hypersensitivity reaction during the IMP infusion, as 
assessed by the investigator, the infusion must be discontinued immediately (see section 5.4) 
and appropriate therapy instituted. Any events believed to be allergic reactions should be 
discussed with the medical monitor.
The site will have the possibility to collect, at the time of the event, additional blood 
specimens using the immune response lab kit, per the laboratory manual. This assessment 
includes plasma histamine, serum tryptase, immunoglobulin E, and complement components. 
10.2
Pregnancy
Although not necessarily considered an adverse event, a pregnancy in a patient in the study 
must be recorded on an Adverse Event Form, as well as on a Pregnancy Form (paper), even if 
no adverse event associated with the pregnancy has occurred. Pregnancies must be reported to 
Lundbeck using the same expedited reporting timelines as those for SAEs.
An uncomplicated pregnancy should not be reported as an SAE; hospitalization for a normal 
birth should not be reported as an SAE. If, however, the pregnancy is associated with an SAE, 
the appropriate serious criterion must be indicated on the Serious Adverse Event Form.
Examples of pregnancies to be reported as SAEs (medically important) are spontaneous 
abortions, stillbirths, and malformations.
The investigator must follow up on the outcome of the pregnancy and report it on a 
Pregnancy Form (paper). The follow-up must include information on the neonate at least up 
until the age of 1 month.
If required by local regulations, the patient and her partner will be asked to sign a separate 
Informed Consent Form in case of pregnancy.
10.3
Recording Adverse Events
Adverse events (including pre-treatment adverse events) must be recorded on an Adverse 
Event Form. The investigator must provide information on the adverse event, preferably with 
a diagnosis, or at least with signs and symptoms; start and stop dates (and start and stop time 
if the adverse event lasts less than 24 hours or occur at the day of the IMP administration); 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 86 of 112
intensity; causal relationship to the IMP; action taken; and outcome. If the adverse event is 
not related to the IMP, an alternative aetiology must be recorded, if available. If the adverse 
event is an overdose, the nature of the overdose must be stated (for example, medication error, 
accidental overdose, or intentional overdose). If the intensity changes during the course of the 
adverse event, this must be recorded on the AE Intensity Log.
If the adverse event is serious, this must be indicated on the Adverse Event Form.
Furthermore, the investigator must fill out a Serious Adverse Event Form and report the SAE 
to Lundbeck immediately (within 24 hours) after becoming aware of it (see section 10.4).
If individual adverse events are later linked to a specific diagnosis, the diagnosis should be 
reported and linked to the previously reported adverse events.
10.4
Reporting Serious Adverse Events (SAEs)
The investigator must report SAEs to Lundbeck immediately (within 24 hours) after 
becoming aware of them by completing a Serious Adverse Event Form.
The initial Serious Adverse Event Form must contain as much information as possible and, if 
more information about the patient’s condition becomes available, the Serious Adverse Event 
Form must be updated with the additional information.
If the investigator cannot report the SAE in Rave®, then he or she must complete and sign the 
Serious Adverse Event Fallback Form and send it to:
Fax:
+45 36 30 99 67
email:
ICSRquery@lundbeck.com
If sent by email, the investigator must ensure that the SAE fallback form is sent password 
protected and that the password is sent in a separate email.
Lundbeck will assume responsibility for reporting SAEs to the authorities in accordance with 
local requirements.
It is the investigator’s responsibility to be familiar with local requirements regarding reporting 
SAEs to the EC or IRB and to act accordingly.
Lundbeck will assume responsibility for reporting SUSARs to the authorities in accordance
with local requirements. In those Member States of the European Union that have 
implemented the European Union Clinical Trials Directive52 and in Norway, Liechtenstein, 
and Iceland, that is, in the countries where unblinded expedited safety reporting is required, 
Lundbeck will also assume responsibility for reporting SUSARs to the ECs.
Lundbeck will assess the expectedness of SAEs and inform the investigator(s) about SUSARs 
in the blinded SUSAR listings.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 87 of 112
10.5
Treatment and Follow-up of Adverse Events
Patients with adverse events must be treated in accordance with usual clinical practice at the 
discretion of the investigator.
Non-serious adverse events must be followed up until resolution or the Completion 
Visit(s)/Safety Follow-up Visit, whichever comes first. At the Completion Visit(s)/Safety 
Follow-up Visit, information on new AEs, if any, and stop dates for previously reported 
adverse events must be recorded.
The investigator must follow up on all SAEs until the patient has recovered, stabilized, or 
recovered with sequelae, and report to Lundbeck all relevant new information using the same 
procedures and timelines as those for the initial Serious Adverse Event Form.
SAEs that are spontaneously reported by a patient to the investigator after the Safety
Follow-up Visit must be handled in the same manner as SAEs that occur during the study.
These SAEs will be recorded in the Lundbeck safety database.
The investigator must follow up on patients with a clinically significant out-of-range clinical 
safety laboratory test value at the Completion Visit (Week 16/Visit 9) or Withdrawal Visit in 
accordance with usual clinical practice. If the clinically significant out-of-range clinical safety 
laboratory test value has not normalized or stabilized or a diagnosis or a reasonable 
explanation has not been established by the Safety Follow-up Visit, the investigator must 
decide whether further follow-up visits are required (this may include an additional medical 
examination and/or additional blood sampling). If further follow-up visits are made, these 
must be documented in the patient’s medical records and not in the eCRF.
Patients who withdraw due to an elevated AST or ALT value (see section 5.4) must be 
followed until the values normalize or stabilize or a diagnosis or a reasonable explanation has 
been established. Additional medical examinations (for example, ultrasound scanning and/or 
sampling for serology, conjugated bilirubin, prothrombin time) should be considered. A 
gastroenterology or hepatology consultation should also be considered.
11 Data Handling and Record Keeping
11.1
Data Collection
11.1.1
Electronic Case Report Forms (eCRFs)
eCRFs will be used to collect all the data related to the study, except the external data 
described in section 11.1.3.
The eCRFs use third party software (Rave®) to capture data via an online system on a 
computer. When the investigator enters data in the eCRF (ideally during the visit or as soon as 
possible [<3 days] thereafter), the data will be recorded electronically in a central database 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 88 of 112
over encrypted lines, and all entries and modifications to the data will be logged in an audit 
trail. Access to the system will only be granted after appropriate and documented training.
Written instructions for using the system will be provided along with the training.
Electronic signatures will be used where signatures are required on pages and/or visits.
Automated data entry checks will be implemented where appropriate; other data will be 
reviewed and evaluated for accuracy by Lundbeck and/or representatives from CRO. All 
entries, corrections, and changes must be made by the investigator or a delegate.
11.1.2
Patient Binders
11.1.2.1
Use of Patient Binders
A Patient Binder will be provided for each patient. The Patient Binder contains different 
types of source documents, organized by visit and type. A ballpoint pen with waterproof ink 
must be used to enter information in the Patient Binder.
11.1.2.2
Serious Adverse Event Fallback Forms
Serious Adverse Event Fallback Forms must be used when the eCRF cannot be accessed.
11.1.3
External Data
The following electronic data will be transferred by the vendor and kept in a secure 
designated storage area outside the eCRF:

eDiary data

ePRO data

ECG results

Clinical Safety Laboratory data

Biobanking data: RNA, Metabolomics/Proteomics, ADA including NAb, DNA (optional)

Biomarker analysis results

IMP quantification results
In case of any electronic Assessments COAs/ePROs the results will be transferred by 
designated vendor.
11.2
Retention of Study Documents at the Site
11.2.1
eCRF Data
If a site closes before the study has been completed, the investigator will continue to have 
read-only access to the eCRF until the study has been completed. After the study has been 
completed, all user access to the eCRF will be revoked. Renewed access to the eCRF will be 
given if corrections or updates to the database are required.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 89 of 112
At the end of the study, the site will be provided with all data related to the site (including 
eCRF data, queries, and the audit trail) using a secure electronic medium; the secure storage 
of these data at the site is the responsibility of the investigator. When confirmation of receipt 
of the data has been received from all sites, all user access to the eCRF will be revoked. If, for 
some reason, the data are not readable for the full retention period (25 years or in accordance 
with national requirements, whichever is longer), the investigator may request that the data be 
re-sent.
11.2.2
Other Study Documents
The investigator must keep the investigator’s set of documents in the investigator TMF for at 
least 25 years after the Clinical Study Report has been approved or in accordance with 
national requirements, whichever is longer. Lundbeck will remind the investigator in writing 
of this obligation when the Clinical Study Report Synopsis is distributed to the site.
If off-site storage is used, a study-specific binder will remain at the site after the other study-
specific documents have been shipped for off-site storage. This binder is considered part of 
the investigator TMF and must be kept in a secure place by the site for the required period of 
time. The binder must contain, at a minimum, the following documents: a copy of the 
Investigator TMF Index, a certified copy of the Patient Identification Code List, and a 
Retrieval Form.
When the required storage period has expired, the documents may be destroyed in accordance 
with regulations.
Data access
During the study, individuals responsible for monitoring the study may view personal 
information of study participants without a code. If this occurs, the information will be kept 
confidential. The patient grants permission for this access by signing the Informed Consent 
Form. These individuals may include the following:

Members of the ethics committee.

Clinical Research Organization (CRO) staff.  For example, the Clinical Research Associate 
(CRA).

National and international supervisory authorities. For example, the FDA, the Healthcare 
and Youth Inspectorate and other government regulatory agencies from other countries.
Data storage
Patient data is stored by the study site for 25 years. Coded personal data from all study 
participants will be archived in the secure systems held by Lundbeck for 25 years or in 
accordance with national requirements, whichever is longer. Please refer to section 11.2.1 of 
the protocol.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 90 of 112
Standard blood samples for safety testing sent to a central laboratory (Medpace Reference 
Laboratories in Belgium) may be stored for a minimum of 1 year up to 3 years after analysis, 
as necessary and will be destroyed within 30 days after the final data transfer.
Samples for eptinezumab quantification, exploratory biomarkers and anti-drug antibody 
assessments will be retained at PRA Netherlands for up to 5 years after reporting of the study.
Samples for future research will stored in a biobank at Azenta, US for a maximum of 
15 years.
Data Destruction
Hardcopy study-specific data will be shredded, and electronic study-specific data will be 
deleted when the required storage period has expired.]  
12 Monitoring Procedures
Prior to allowing patients to participate in the study, the investigator must sign a source data 
agreement that identifies the source documents (original documents, data, and records) at the 
site. The document will also list which data may be recorded directly on the eCRFs.
Only patients with eCH may be enrolled in the study. The patient’s medical records are the 
most comprehensive source to document the patient’s diagnosis. Thus, it is required that the 
investigator obtains copies of medical records for each patient. In case the investigator does 
not have medical records for a patient at his/her own clinic, the investigator must obtain 
copies/written summary of relevant medical records from the previous treating physician and 
include the pertinent documentation in the patient’s medical records at the site. If original 
medical records are unavailable, any properly documented communication with the treating 
physician, letters, written summaries, photocopies of medical records, pharmacy records and 
specific letter templates may be used to document the eCH diagnosis and previous acute and 
preventive medication use for eCH, covering a period of at least 12 months prior to Screening 
Visit 1 and general medical history prior to the study. Information about changes in the 
patient’s medical history, treatment for eCH and other concomitant medication that might 
occur between Screening Visit 1 and the Screening Visit 2 must be obtained, using the above 
described modalities and documented in the patient’s medical records at site.
During the study, the CRA will visit the site to ensure that the protocol is being adhered to 
and that all issues are being recorded, to perform source data verification, and to monitor IMP 
accountability. The visit intervals will depend on the outcome of the remote monitoring of the 
eCRFs, the site’s recruitment rate, and the compliance of the site to the protocol and Good 
Clinical Practice. In addition, the CRA will be available for discussions by telephone.
Source data verification requires that the CRA be given direct access to all the source 
documents. Direct access includes permission to examine and verify any records that are 
important for the evaluation of the study.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 91 of 112
If the site is closed to the CRO monitor due to COVID-19 or other site restrictions, remote 
source data verification may be done, if allowed per local and site regulations. This includes 
the ability for Sponsors/site monitors to conduct full and thorough source document 
verification with access to electronic medical records (EMR).
13 Audits and Inspections
Authorized personnel from Medical, Regulatory and Clinical Quality Assurance, 
H. Lundbeck A/S, and quality assurance personnel from business partners may audit the study 
at any time to assess compliance with the protocol and the principles of Good Clinical 
Practice and all other relevant regulations.
The investigator must be aware that representatives from regulatory authorities may also wish 
to inspect source data, such as medical records. The investigator must notify Lundbeck, 
without delay, of an announced inspection by a regulatory authority.
During audits and inspections, the investigator must permit direct access to all the source 
documents, including medical records and other documents pertinent to the study.
During audits and inspections, the auditors and inspectors may request relevant parts of 
medical records. No personal identification apart from the screening or randomization 
numbers will appear on these copies.
Patient data will not be disclosed to unauthorized third parties, and patient confidentiality will 
be respected at all times.
14 Protocol Compliance
Lundbeck has a “no-waiver” policy, which means that permission will not be given to deviate 
from the protocol.
If a deviation occurs, the investigator must inform the CRA and they must review, discuss, 
and document the implications of the deviation.
15 Study Termination
Lundbeck or a pertinent regulatory authority may terminate the study or part of the study at 
any time. The reasons for such action may include, but are not limited to:

safety concerns

proven lack of efficacy of anti-CGRP agents in clinical trials sponsored by Lundbeck or 
competitors 

results of the planned interim analysis
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 92 of 112
[Country Specific Amendment 1 for Germany:

safety concerns that negatively impact the benefit/risk balance of eptinezumab treatment 
for the study population

proven lack of efficacy of anti-CGRP agents in clinical trials sponsored by Lundbeck or 
competitors

results of the planned interim analysis

revocation of the positive opinion or approval of the entire study

a necessary adjustment of the maximum insured amount is not possible]
[Country Specific Amendment 1 for Netherlands:
Lundbeck or a pertinent regulatory authority may terminate the study or part of the study in 
the Netherlands at any time.  The reasons for such action may include, but are not limited to:

safety concerns

proven lack of efficacy of anti-CGRP agents in clinical trials sponsored by Lundbeck or 
competitors 

results of the planned interim analysis

the approval by the Ethics Committee in charge of the Clinical Trial is irrevocably 
revoked;

it can be reasonably concluded that the Clinical Trial must be terminated in the interests of 
the health of the Clinical Trial Subjects;

it becomes apparent, following confirmation of the Ethics Committee that continuation of 
the Clinical Trial cannot serve a scientific purpose, and this is notified to the Ethics 
Committee;

the Sponsor and/or the Institution (study site) become or are declared insolvent or a 
petition in bankruptcy has been filed against it or if one of them is dissolved;

the principal investigator is no longer able to perform the duties of principal investigator, 
and no replacement can be found by mutual consent. This will result in closure of the study 
site.

one of the Parties fails to comply with the obligations arising from the Agreement and, if 
capable of remedy, is not remedied within 30 days after receipt of written notice from the 
other Party specifying the non-compliance and requiring its remedy, unless failure to 
comply is not in reasonable proportion to the premature termination of the Clinical Trial.

if circumstances beyond the control of the sponsor, investigator or funder make it 
unreasonable to require the study's continuation.
The study or part of the study will be terminated in the Netherlands if it is temporarily 
suspended for reasons of subjects’ safety and the accredited METC gives a negative decision 
after assessing the reasons that led to the temporary suspension.]
If the study is terminated or suspended, the investigator must promptly inform the patients 
and ensure appropriate therapy and follow-up. Furthermore, the investigator and/or Lundbeck
must promptly inform the EC or IRB and provide a detailed written explanation. The 
pertinent regulatory authorities must be informed in accordance with national regulations.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 93 of 112
If the risk/benefit evaluation changes after the study is terminated, the new evaluation must be 
provided to the EC or IRB if it will have an impact on the planned follow-up of the patients 
who participated in the study. If so, the actions needed to protect the patients must be 
described.
16 Statistical Methodology
16.1
Responsibilities
An independent CRO will perform the unblinded interim analysis. Biostatistics, 
H. Lundbeck A/S, will perform the statistical analyses for the clinical study report.
16.2
Analysis Sets
The following analysis sets will be used to analyse and present the data:

all-patients-randomized set (APRS) - all randomized patients

all-patients-treated set (APTS) - all patients in the APRS who received infusion with 
double-blind IMP

all-patients-treated at interim set (APTS_IN) – all patients in the APRS who were among 
the first 204 that received infusion with double-blind IMP. Patients in the APTS that were 
infused on the same date, but after the first 204 will also be included.   
The patients and data will be classified into the analysis sets according to these definitions at a 
Classification Meeting. For the interim analysis, the meeting will be held after the study 
database for the interim analysis has been released but before the unblinding for the interim 
analysis.
When all in patients in APRS have had the chance of completing the Placebo-controlled 
Period (Visit 6/Week 4), data collected in the Placebo-controlled Period will be cleaned and 
locked. A Classification Meeting will be held after the database release for the reporting of 
the Placebo-controlled Period but before the blind has been broken. Patients included in the 
interim cut-off will not be re-classified. Analyses specified in the SAP for data collected in 
the Placebo-controlled Period will then be performed. After all patients have completed the
study, data will be cleaned and locked, the database will be released and the remaining 
analysis in the SAP will be performed.
Investigators and patients will be informed about which treatment (eptinezumab 400 mg or 
placebo) the patients received in the Placebo-controlled Period only after the last patient has 
completed the study. Efficacy analyses for the interim analysis will be based on APTS_IN, 
and the final efficacy analyses of the Placebo-controlled Period will be based on APRS. 
Demographics, Baseline characteristics, and safety tables (including exposure and 
medications) will be based on APTS.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 94 of 112
16.3
Descriptive Statistics
In general, summary statistics (n, arithmetic mean, standard deviation, median, lower and 
upper quartiles, minimum and maximum values) will be presented for continuous variables 
and counts and, if relevant, percentages will be presented for categorical variables.
The last day of the cluster headache bout is defined as the last day with cluster headache 
attacks of moderate or severe pain or the last day when abortive medication was used
(whichever is the latest), followed by a 2-week period free of cluster headache attacks or 
cluster headache attacks with only mild pain, not requiring the use of abortive medication. 
Resolution of the cluster headache bout is defined as the day after the last day of the cluster 
headache bout.
16.4
Patient Disposition
Patient disposition will be summarized by treatments and include the number of patients in 
each analysis set who completed or withdrew from treatment, as well as the number of 
patients in each analysis set (APRS, APTS, APTS_IN, and).
The number of patients who withdrew will be summarized by period and treatments and
primary reason for withdrawal as well as by period and treatments and all reasons for 
withdrawal.
16.5
Demographics and Baseline Characteristics
Demographics (sex, age, and race), baseline characteristics (height, weight, and BMI), 
baseline efficacy variables, and other disease characteristics will be summarized by period 
and treatments.
16.6
Recent and Concomitant Medication
Recent and concomitant medication will be summarized by anatomical therapeutic chemical 
(ATC) code and generic drug name by period and treatments.
16.7
Exposure
All patients in the APTS are expected to receive at least one infusion of the IMP. The number 
of patients infused and patients who had their infusion interrupted will be summarised by visit
and treatment. Patients whose infusion took more than 45 mins and patients who had their 
infusion interrupted will be listed with period and treatment, infusion start date/time and end 
date/time, infusion related reactions, and reasons if any.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 95 of 112
16.8
Efficacy Analyses
16.8.1
General Efficacy Analysis Methodology
Unless otherwise specified, all efficacy analyses will be based on the APRS.
All tables and graphs will be presented by treatment.
All p-values will be based on two-sided tests; the confidence intervals (CIs) will be two-sided; 
and the endpoints will be presented with 95% CIs. The endpoints not included in the testing 
strategy will be presented with p-values and 95% CIs.
Apart from the exploratory endpoint ‘Time from first infusion of eptinezumab to resolution of 
cluster headache bout within 16 weeks’ which will only be presented for patients randomised 
to eptinezumab during the placebo-controlled phase, the efficacy data from the Delayed start 
period (excluding the safety follow-up period) will be presented descriptively by treatment.
16.8.1.1
Primary Estimand
The primary estimand will be the mean difference in change from Baseline in the number of 
weekly attacks (Weeks 1-2) between patients with episodic cluster headache treated with 
eptinezumab and placebo, without use of transitional treatment, and regardless of use of 
abortive or preventive medication, and infusion interruption or termination before full dose is 
received.
Intercurrent Events
The following intercurrent events, occurring after treatment initiation and potentially affecting 
either the interpretation or the existence of the measurements associated with the clinical 
question of interest, are considered:

Abortive medication for cluster headache (Triptans or Oxygen)

Preventive medication for cluster headache (Classified by investigator clinician among the 
concomitant medication)

Transitional treatment for cluster headache (GON block and oral steroids)

Interruption of IMP: Infusion stopped prematurely
Attributes of the primary estimand
The primary estimand has the following attributes:

The treatment condition of interest will be the comparison of eptinezumab 400 mg to 
placebo without the use of transitional treatment, and with or without the use of abortive or 
preventive medication for cluster headache

The population of interest will be all patients with episodic cluster headache that fulfil the 
inclusion and exclusion criteria
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 96 of 112

The endpoint to be obtained to address the clinical question is change from Baseline in 
the number of weekly attacks (Weeks 1-2)

The other intercurrent events: use of transitional treatment or interruption or prematurely 
stopping IMP infusion will be addressed by treatment policy strategies 

The population level summary will be the mean difference in the primary endpoint 
between eptinezumab 400 mg and placebo.
16.8.2
Strategies for Addressing Intercurrent Events in Primary Estimand
Clinically relevant strategies to manage the intercurrent events are selected based on the 
following hypothesis for likely outcomes given the intercurrent events.
It is hypothesised, that for an individual patient, daily attacks may increase a little early in the 
bout, i.e. during Screening Period 2 and potentially during Week 1, but after which the daily 
attacks reach a “plateau” for a period of time and start decreasing in frequency and intensity 
indicating that the bout is coming to an end. The minimum expected duration of CH bout in 
this study is 6 weeks. Thus, if effective the active treatment should result in a decrease in the 
symptoms level, and more so than placebo regardless of whether the patients continue to 
report data in the eDiary for the study, since the infused drug continues to be available in the 
body well beyond the first 2 weeks. 
Therefore, if penalization is required it is not possible to use baseline observation carried 
forward, since baseline values could be better than Week 1 values. For this reason,
penalization will be done using the imputation according to the placebo treatment.
Use of abortive rescue medication 
Abortive medication for an individual attack is typically taken after the start of the attack and 
may reduce the severity and duration of the attack, for which it was used, but is not expected 
to have a preventive effect on future attacks even if on the same day.
Use of abortive medication for attacks will be addressed with a treatment policy strategy, 
using the reported number of attacks regardless of any abortive medication used.
Use of preventive medication
Preventive medications usually require up-titration (approximately 2 weeks) before the effect 
is established, hence these are not expected to affect the symptom level during the first 
2 weeks of the Placebo-Controlled period.
Use of preventive medication will be addressed with a treatment policy strategy, using the 
reported observations regardless of any preventive medication initiated.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 97 of 112
Use of transitional treatment for eCH
Transitional treatments, such as GON block and oral steroids, are expected to impact the 
number of future attacks with an almost immediate effect.
Use of transitional treatment for cluster headaches will be addressed using a hypothetical 
strategy, assessing effect as if no transitional treatment would be available. Under these 
hypothetical circumstances it is assumed that the effect would be similar to other patients with 
similar previous scores on the same randomised treatment.
Interruption of infusion with IMP
The primary estimand targets the effect seen regardless of interruption or prematurely 
stopping IMP infusion. This is considered a conservative approach, as such disturbances are 
mainly expected to affect the active treatment. Interruption or termination of infusion will be 
addressed using a treatment policy strategy.
16.8.3
Primary Analysis of the Primary Endpoint
The clinical question of interest is whether the number of attacks is reduced more with 
eptinezumab than with placebo during the first 2 weeks after infusion.
The primary endpoint, that will address the clinical question of interest, will be the change 
from Baseline in the number of weekly attacks (Weeks 1-2). The endpoint is based on eDiary 
data on attacks and the average number of weekly attacks across Week 1 and Week 2 will be 
estimated as presented below.
The strategy for imputation of missing data is given below and in details in the SAP:
Weekly scores are calculated using pro-rating, when data has been observed for at least 4 out 
of 7 days, with the weekly score = the average daily score x 7.
The primary analysis will use a placebo-based multiple imputation (pMI) method. 
Specifically, an analysis will be performed using a pattern-mixture model (PMM), in which 
after application of the prorating rule to data, any missing weekly scores will be imputed 
using a sequential regression-based multiple imputation method, based on the imputation 
models established from the placebo group.
The pMI will generate 200 simulated data sets with complete assessment of number of weekly 
attacks for Weeks 1, 2, 3, and 4. Each of these 200 data sets will be analysed using the 
following MMRM model:
The MMRM model based on data from all 4 weeks in the PBO-controlled period will include 
the following fixed effects: week (1, 2, 3, 4), country, and treatment as factors, baseline score 
as a continuous covariate, treatment-by-week interaction, and baseline score-by-week 
interaction. An unstructured variance structure will be used to model the within-patient errors. 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 98 of 112
The mean difference between eptinezumab and placebo in the Change from Baseline in the 
number of weekly attacks (Weeks 1-2) will be estimated based on least square means for the 
treatment-by-week-interaction, using weights (1/2 1/2 0 0) for the eptinezumab by week 
estimates, and weights (-1/2 -1/2 0 0) for the placebo by week estimates.
The 200 results will be weighted together using Rubin’s rule to obtain a pMI estimate, 
confidence interval, and p-value.
16.8.4
Details are provided in the SAP.Sensitivity Analyses of the Primary Endpoint
The impact of missing data in the derivation of the number of weekly attacks averaged across 
Weeks 1-2 and the impact of the use of transitional treatment will be evaluated by applying 
different methods of imputation. Details will be described in the SAP. 
16.8.5
Analysis of the Key Secondary Endpoints
Key secondary endpoints based on eDiary will be imputed along the lines used for the 
primary endpoint. Details will be provided in the SAP.
The continuous key secondary endpoints (Change from Baseline in the number of weekly 
times an abortive medication was used (Weeks 1-2), and Change from Baseline in the number 
of weekly days with <3 attacks per day (Weeks 1-2)) will be analysed using the MMRM 
model presented in the section on primary analysis using the baseline value of the variable as 
baseline. 
The Change from Baseline in the number of daily attacks (Days1-3) will be analysed using an 
analysis of covariance (ANCOVA) including treatment and country as factors and baseline 
number of weekly attacks as covariate.  
The Number of attacks starting <=24 hours after the start of the first infusion of IMP will be 
analysed using an ANCOVA with treatment and country as factors and with the baseline 
number of weekly attacks as covariate.
When using the terminology Weeks 1-2 or Days 1-3 for example, the average across the first 
two weeks or the first three days is measured.
Response used as a key secondary endpoint will be analysed using logistic regression where 
region and treatment are included as fixed factors and baseline number of weekly attacks is 
included as covariate.
Time from first infusion of IMP to resolution of cluster headache bout within the first 4 weeks 
will be analysed using a Cox regression model with baseline number of weekly attacks as 
covariate and treatment and duration of current CH bout until infusion (1 or 2 weeks of 
screening period 2) as fixed factors.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 99 of 112
16.8.6
Testing Strategy
Primary endpoint

Change from Baseline in the number of weekly attacks (Weeks 1-2)
Key secondary endpoints

Response: 50% reduction from Baseline in the number of weekly attacks (Weeks 1-2)

Change from Baseline in the number of weekly times an abortive medication was used 
(Weeks 1-2)

Change from Baseline in the number of daily attacks (Days 1-3)

Change from Baseline in the number of weekly days with < 3 attacks per day (Weeks 1-2)

Time from first infusion of IMP to resolution of cluster headache bout (within the first 4 
weeks)

Number of attacks starting <=24 hours after the start of the first infusion of IMP
A two-sided significance level of 0.05 will be used for the formal testing strategy.
The testing strategy will be a sequence of tests, testing one endpoint at a time. Only if one 
step has shown a statistically significant effect will the formal testing continue with the next 
step, thus ensuring protection of the type 1 error. The steps are described below.
Step 1
Test the primary endpoint using a 5.0% significance level. If the primary endpoint shows an 
advantageous effect of eptinezumab compared to placebo, the effect seen for the primary 
endpoint is considered statistically significant, and the testing continues with the next step.
Step 2
Test the first key secondary endpoint using a 5.0% significance level. If the first key 
secondary endpoint shows an advantageous effect of eptinezumab compared to placebo, the 
effect seen for the first key secondary endpoint is considered statistically significant, and the 
testing continues with the next step for the second key secondary endpoint.
Step 3
The steps for testing the key secondary endpoints in the order stated in the beginning of this 
section continues until a p-value >= 0.05 is encountered or all 6 key secondary endpoints are 
found to be statistically significant.
16.8.7
Analysis of the Secondary Endpoints
The continuous secondary endpoints (with the exception of PGIC) will be analysed using a 
MMRM model similar to the one described in the primary endpoint section.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 100 of 112
The PGIC score will be analysed using an MMRM with number of attacks in the Screening 
Period 2 as covariate instead of baseline score.
Tables displaying the counts and percentage of answers to each category of response options 
for each item of EQ-5D-5L will be presented by visit and treatment. Furthermore, shift tables 
displaying for each item in EQ-5D-5L the number and percentage of patients who decreased, 
increased or had no change from baseline in the item score will be provided by visit and 
treatment.
Descriptive tables displaying the distribution of answers to the items in HCRU at each visit 
will be provided by treatment.
The binary secondary endpoints (response) will be analysed in a similar way as for the key 
secondary endpoint using a logistic regression with region and treatment included as fixed 
factors and baseline number of weekly attacks as a covariate.
16.8.8
Analysis of the Exploratory Endpoints
The continuous exploratory endpoints will be analysed using a MMRM model similar to the 
one described in the primary endpoint section.
The binary exploratory endpoint (response) will be analysed in a similar way as for the key 
secondary endpoint using a logistic regression with region and treatment included as fixed 
factors and baseline number of weekly attacks as a covariate.
A Kaplan-Meier plot of time from first infusion of eptinezumab to resolution of cluster bout 
within 16 weeks will be provided for the 400mg eptinezumab treatment.
The ANCOVA model used for analysing number of attacks starting within 24 hours after the 
start of the first infusion will be implemented for data assessed in 3 different time intervals 
after the first infusion giving 3 different treatment estimates: one for attacks starting >0 and 
<= 8 hours after the first infusion of IMP, one for attacks starting >8 and <= 16 hours after 
first infusion of IMP, and one for attacks starting >16 and <=24 hours after the first infusion
of IMP.
The following endpoints will be presented using descriptive statistical analyses:

Use (yes/no) of abortive medication (triptans or O2) for each of Weeks 5 to 16

Use (yes/no) of preventive medication for each of Weeks 1 to 16

Use (yes/no) of transitional treatment for each of Weeks 5 to 16 

Change from Baseline in the EQ-5D-5L Visual Analogue Scale (VAS) score at Weeks 8 
and 16

Patient Global Impression of Change (PGIC) score at Weeks 8 and 16

Number of weekly attacks for each of Weeks 5 to 16

Severity of pain (average per attack over a week) based on a 5-point self-rating pain 
severity scale for each of Weeks 5 to 16
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 101 of 112
16.8.9
Analysis of Subgroups
Details of subgroup analyses will be specified in the SAP.
16.9
Safety Analyses
16.9.1
Analysis of Adverse Events
Adverse events will be classified according to the time of onset of the adverse event:

pre-treatment adverse event – an adverse event that starts on or after the date the patient 
signed the Informed Consent Form and prior to the date and time of first dose of IMP

treatment-emergent adverse event (TEAE) – an adverse event that starts during or after 
administration of the first dose of IMP, or a pre-treatment adverse event that increases in 
intensity or becomes serious during or after administration of the first dose of IMP
Adverse events, sorted by system organ class (SOC) and preferred term, will be summarized 
by period and treatment.
Allocation of TEAEs to Study Periods
TEAEs will be allocated to study periods (these will be defined in the Statistical Analysis 
Plan).
16.9.2
Analysis of Other Safety Endpoints
The clinical safety laboratory test values, vital signs, weight, and ECG parameter values will 
be summarized by period and treatment. Potentially clinically significant (PCS) values will be 
flagged and summarized.
The number of patients with ADA will be summarised by period and treatment. The number 
of patients with NAbs will be summarised by period and treatment.
Non-suicidal self-injury behaviour (considered separately) and no suicidal ideation or 
behaviour or the worst suicidal ideation or behaviour will be summarised by period and 
treatment.
16.10 Interim Analyses
When 204 patients have been randomised, have received IMP and have had the chance of 
completing the Visit 6 (Week 4), the data will be cleaned and an interim analysis will be 
performed for the APTS_IN. If the estimated treatment effect is less than 1/3 of the expected 
effect size (3.00/3 = 1). Lundbeck may decide to stop the study for futility.
The interim analysis will be performed by an independent CRO, and the evaluation methods 
used in the interim analysis is the same as for the primary endpoint.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 102 of 112
The SAP will be finalized prior to the interim analyses.
The independent CRO will inform a predefined group of Lundbeck employees whether the 
criterion for the interim futility have been met or not. No further details of the interim analysis 
results will be provided.
Details of the interim process will be described in a separate Interim Analysis Charter.
Details of the statistical analysis for the interim analysis will be described in an Interim 
Statistical Analysis Plan.
Further details will be described in an Interim Statistical Analysis Plan that will be prepared 
by Biostatistics, H. Lundbeck A/S, before the study is partially unblinded.
16.11 Sample Size and Power
Goadsby (2019)35 describes a study in eCH, where the first 4 weeks have a design similar to
this study. The difference between galcanezumab and placebo in change from baseline in 
weekly frequency of attacks at Week 1 is estimated at -1.5 attacks, and at Week 2 is estimated 
at -4.4 attacks. The average difference to placebo across Week 1 and Week 2 is estimated at 
3.0. Based on the CI presented in the publication, the SD at Week 1 is estimated at 9.2 and the 
SD at Week 2 is estimated at 11.1. Assuming that the correlation between Week 1 and 
Week 2 is 0.56, the SD for the average of Week 1 and 2 will be SD = 9.0. 
Assuming a difference of eptinezumab to placebo of -3.0 attacks with an SD = 9.0, 144 
patients per treatment will provide 80% power for seeing an effect using a two-sided
5.0% significance level. Since the estimated treatment difference may be slightly decreased 
due to the use of pMI, an additional 5% of patients have been added. This yields a total of 
152 patient per treatment.
16.12 Statistical Analysis Plan
A Statistical Analysis Plan describing the handling of data issues and the planned statistical 
analyses in more detail will be prepared by Biostatistics, H. Lundbeck A/S, before the study is 
unblinded.
17 Clinical Study Report and Publications
17.1
Data Ownership
The data collected in this study are the property of Lundbeck.
17.2
Clinical Study Report
Upon completion of the study, a Clinical Study Report will be prepared by Regulatory 
Medical Writing, H. Lundbeck A/S.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 103 of 112
17.3
Summary of Clinical Study Results
Upon completion of the study and when the study results are available, the patient has the 
right to be informed by the investigator about the overall study results.
17.4
Publications
The results of this study will be submitted for publication, in accordance with the Lundbeck 
policy and regardless of the study outcome.
Lundbeck will submit results information:

to ClinicalTrials.gov

to EudraCT
The primary publication based on this study must be published before any secondary 
publications. Authors of the primary publication must fulfil the criteria defined by the 
International Committee of Medical Journal Editors (ICMJE).53
18 Indemnity and Insurance
In the event of study-related injuries or deaths, insurance for the patients and indemnity of the 
investigators and those of their employees, servants, or agents whose participation in this 
study has been documented are provided. Insurance and liability will be in accordance with 
applicable laws and Good Clinical Practice.
19 Finance
19.1
Site Agreements
The financial agreements with each site are addressed in one or more documents. Both parties 
must sign the agreements before each site is initiated.
19.2
Financial Disclosure
All the investigators, including sub-investigators, and raters participating in the study must 
complete a Financial Disclosure Form.
19.3
Equipment
Equipment owned or rented by Lundbeck that has been provided to the sites for use during the 
study must be returned at the end of the study.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 104 of 112
References
1.
International Headache Society (IHS), Headache Classification Committee. The International 
Classification of Headache Disorders, 3rd edition 2018 (ICHD-3 2018).
2. 
Jensen RM, Lyngberg A, Jensen RH. Burden of Cluster headache. Cephalalgia. 2007 Jun;27(6): 
535-541.
3. 
Ford JH, Nero D, Kim G, Chu BC, Fowler R, Ahl J, Martinez JM. Societal burden of cluster 
headache in the United States: a descriptive economic analysis. J Med Econ. 2018 Jan;21(1):107-
111.
4. 
Fischera M, Marziniak M, Gralow I, Evers S. The incidence and prevalence of cluster headache: a 
meta-analysis of population-based studies. Cephalalgia. 2008 Jun;28(6):614-618.
5. 
Lund N, Barloese M, Petersen A, Haddock B, Jensen R. Chronobiology differs between men and 
women with cluster headache, clinical phenotype does not. Neurology. 2017 Mar;88(11):1069-
106.
6. 
Torelli P, Manzoni GC. Pain and behaviour in cluster headache. A prospective study and review 
of the literature. Funct Neurol. 2003 Oct-Dec;18(4):205-210.
7. 
Ekbom K, Monstad I, Prusinski A, Cole JA, Pilgrim AJ, Noronha D. Subcutaneous sumatriptan in 
the acute treatment of cluster headache: a dose comparison study. The Sumatriptan Cluster 
Headache Study Group. Acta Neurol Scand. 1993 Jul;88(1):63-69.
8. 
Law S, Derry S, Moore RA. Triptans for acute cluster headache. Cochrane Database Syst Rev. 
2013 Jul;(7):CD008042.
9.
Treatment of acute cluster headache with sumatriptan. The Sumatriptan Cluster Headache Study 
Group. N Engl J Med. 1991 Aug;325(5):322-326.
10. Cohen AS, Burns B, Goadsby PJ. High-flow oxygen for treatment of cluster headache: a 
randomized trial. JAMA. 2009 Dec;302(22):2451-2457.
11. Fogan L. Treatment of cluster headache. A double-blind comparison of oxygen v air inhalation. 
Arch Neurol. 1985 Apr;42(4):362-363.
12. Kudrow L. Response of cluster headache attacks to oxygen inhalation. Headache. 1981 
Jan;21(1):1-4.
13. Petersen AS, Barloese MC, Lund NL, Jensen RH. Oxygen therapy for cluster headache. A mask 
comparison trial. A single-blinded, placebo-controlled, crossover study. Cephalalgia. 2017 
Mar;37(3):214-224.
14. Afridi SK, Shields KG, Bhola R, Goadsby PJ. Greater occipital nerve injection in primary 
headache syndromes--prolonged effects from a single injection. Pain. 2006 May;122(1-2):126-
129.
15. Leroux E, Valade D, Taifas I, Vicaut E, Chagnon M, Roos C, Ducros A. Suboccipital steroid 
injections for transitional treatment of patients with more than two cluster headache attacks per 
day: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2011 Oct;10(10):891-
897.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 105 of 112
16. Petersen AS, Barloese MCJ, Snoer A, Soerensen AMS, Jensen RH. Verapamil and Cluster 
Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives. 
Headache. 2019 Sep;59(8):1198-1211.
17. Tfelt-Hansen PC, Jensen RH. Management of cluster headache. CNS Drugs. 2012 Jul;26(7):571-
580.
18. Huang WY, Lo MC, Wang SJ, Tsai JJ, Wu HM. Topiramate in prevention of cluster headache in 
the Taiwanese. Neurol India. 2010 Mar-Apr;58(2):284-287.
19. May A, Schwedt TJ, Magis D, Pozo-Rosich P, Evers S, Wang SJ. Cluster headache. Nat Rev Dis 
Primers. 2018 Mar;4:18006.
20. Edvinsson L, Goadsby PJ. Neuropeptides in migraine and cluster headache. Cephalalgia. 1994
Oct;14(5):320-327.
21. Snoer A, Vollesen ALH, Beske RP, Guo S, Hoffmann J, Fahrenkrug J et al. Calcitonin-gene 
related peptide and disease activity in cluster headache. Cephalalgia. 2019 Apr;39(5):575-584.
22. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of 
humans during migraine headache. Ann Neurol. 1990 Aug;28(2):183-187.
23. Vollesen ALH, Snoer A, Beske RP, Guo S, Hoffmann J, Jensen RH, Ashina M. Effect of Infusion 
of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial.
JAMA Neurol. 2018 Oct;75(10):1187-1197.
24. H. Lundbeck A/S. Investigator’s Brochure: eptinezumab. current version.
25. Gupta R, Levin E, Wu JJ, Koo J, Liao W. An update on drug-drug interactions with biologics for 
the treatment of moderate-to-severe psoriasis. J Dermatolog Treat. 2014;25(1):87-89.
26. Dodick DW, Goadsby PJ, Silberstein SD, Lipton RB, Olesen J, Ashina M, et al. Safety and 
efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent 
episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. 
Lancet Neurol. 2014;13(11):1100-1107.
27. Dodick DW, Lipton RB, Silberstein S, Goadsby PJ, Biondi D, Hirman J, et al. Eptinezumab for 
prevention of chronic migraine: A randomized phase 2b clinical trial. Cephalalgia. 
2019;39(9):1075–1085.
28. Ashina M, Saper J, Cady R, Schaeffler BA, Biondi DM, Hirman J, et al. Eptinezumab in episodic 
migraine: A randomized, double-blind, placebo-controlled study (PROMISE-I). Cephalagia. 
2020;0(0):1-14.
29. Lipton RB, Goadsby PJ, Smith J, Schaeffler BA, Biondi DM, Hirman J, et al. Efficacy and safety 
of eptinezumab in patients with chronic migraine. PROMISE-2. 2020: 10.1212/ 
WNL.0000000000009169.
30. Spierings E, Biondi D, Hirman J, Horblyuk R, Cady R. Reduced impact of headaches after 
migraine preventive treatment with eptinezumab in patients with chronic migraine: Results from 
the PREVAIL open-label safety study. Presented at: 2019 American Headache Society Annual 
Meeting. July 11-14, 2019; Philadelphia, PA. Poster 16.
31. Kudrow D, Berman G, Kassel E, et al. Eptinezumab treatment for migraine prevention reduces 
migraine disability in patients with chronic migraine: An analysis from the PREVAIL open-label 
safety study. Presented at: 2019 American Headache Society Annual Meeting. July 11-14, 2019; 
Philadelphia, PA. Poster 17.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 106 of 112
32. ClinicalTrials.gov Identifier: NCT04152083.
33. Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and 
pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548-558. 
34. HIS 1998 guidelines for Cluster headache.
35. Goadsby PJ, Dodick DW, Leone M, Bardos JN, Oakes TM, Millen BA et al. Trial of 
Galcanezumab in Prevention of Episodic Cluster Headache. N Engl J Med. 2019 Jul;381(2):132-
141.
36. World Medical Association (WMA). Declaration of Helsinki: Ethical principles for medical 
research involving human subjects. [Internet] 
wma.net/en/30publications/10policies/b3/index.html.
37. ICH. ICH Harmonised Guideline E6(R2): Integrated addendum to ICH E6(R1): Guideline for 
Good Clinical Practice. November 2016.
38. International Headache Society (IHS). Guidelines for controlled trials of drugs in cluster 
headache. 1995. 
39. Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of 
galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 
randomized controlled clinical trial. Cephalalgia. 2018 Jul;38(8):1442-1454.
40. Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic 
migraine: The randomized, double-blind, placebo-controlled REGAIN study. Neurology. 2018 
Dec;91(24):e2211-e2221.
41. Caceres MC, Guerrero-Matin J, Pérez-Civantos D, Palomo-Lopez P, Delgado-Mingorance JI, 
Duran-Gomez N. The importance of early identification of infusion-related reactions to 
monoclonal antibodies. Ther Clin Risk Manag. 2019 Aug 1;15:965-977.
42. ICH. ICH Harmonised Tripartite Guideline E5(R1): Ethnic factors in the acceptability of foreign 
clinical data. 5 February 1998.
43. United States Food and Drug Administration (US FDA). Guidance for Industry, Investigators, 
and Institutional Review Boards: Conduct of clinical trials of medical products during the 
COVID-19 public health emergency. March 2020 (updated on December 4, 2020). 
44. European Medicines Agency (EMA). Guidance on the management of clinical trials during the 
COVID-19 (coronavirus) pandemic. Version 4. 04 February 2021.
45. European Parliament and Council of the European Union. Regulation (EU) 016/679: Protection of 
natural persons with regard to the processing of personal data and on the free movement of such 
data, and repealing Directive 95/46/EC (General Data Protection Regulation). 27 April 2016. 
Official Journal of the European Union L119, 4 May 2016.
46. Lipton RB, Micieli G, Russel G et al. The IHS Members’ Handbook 1997/98: Guidelines for 
controlled trials of drugs in cluster headache. First edition: International Headache Society 
Committee on Clinical Trials in Cluster Headache.
47. Crawford B, Burgess S, Burell A et al. Development and validation of the sleep impact scale for 
insomnia. Value in Health, 2007;10:A304. 
48. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of Life 
Research. 2011;20:1727–1736.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 107 of 112
49. Reilly MC, Zbrozek AS, Dukes, EM. The validity and reproducibility of a work productivity and 
activity impairment instrument. Pharmacoeconomics. 1993;4(5):353–365.
50. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The 
ColumbiaSuicide Severity Rating Scale: initial validity and internal consistency findings from 
three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168:1266–1277.
51. ICH. ICH Harmonised Tripartite Guideline E2A: Clinical safety data management: definitions 
and standards for expedited reporting. October 1994.
52. European Parliament and Council of the European Union. Directive 2001/20/EC: Approximation 
of the laws, regulations and administrative provisions of the Member States relating to the 
implementation of Good Clinical Practice in the conduct of clinical trials on medicinal products 
for human use. 4 April 2001. Official Journal of the European Communities L 121, 1 May 2001.
53. International Committee of Medical Journal Editors (ICMJE). Recommendations for the conduct, 
reporting, editing, and publication of scholarly work in medical journals. [Internet] 
icmje.org/icmje-recommendations.pdf. December 2017.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 108 of 112
Appendix I
Clinical Study Protocol
Authentication and Authorization
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 109 of 112
Clinical Study Protocol
Authentication and Authorization
Study title:
Interventional, randomized, double-blind, parallel-group, placebo-controlled 
delayed-start study to evaluate the efficacy and safety of eptinezumab in patients 
with episodic Cluster Headache
Study No.:
19386A
Edition No.:
5.0
Date of edition:
03 April 2023
This document has been signed electronically. The signatories are listed below.
Authentication
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
International study manager:
Clinical research scientist:
Head of Biostatistics:
Head of Global Medical Safety:
Authorization
I hereby confirm that I am of the opinion that the ethical and scientific basis of this study is sound.
Therapeutic Area Lead:
Bjørn Sperling
PPD
PPD
PPD
PPD
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 110 of 112
Appendix II
Recent and Concomitant Medication
Disallowed or Allowed with Restrictions
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 111 of 112
Recent and Concomitant Medication:
Disallowed or Allowed with Restrictions 
In the table below, recent and concomitant medications that are disallowed or allowed with 
restrictions with respect to their use prior to or during the study are listed.
Drug Class
Details
Any investigational drug
Do not use within 30 days or 5 plasma half-lives (whichever is longer) 
prior to the Screening Visit 2.
Anticonvulsants 
Allowed with restrictions:
For preventive treatment for CH, see Cluster Headache Therapies
For indications other than cluster headache: 
Allowed if prescribed for indications other than epilepsy.
Cluster Headache Therapies
Abortive treatment
The following abortive therapy for cluster headache attack is allowed:
high-flow oxygen; 
oral triptans, sumatriptan subcutaneous injection; sumatriptan nasal 
spray; zolmitriptan nasal spray; 
acetaminophen, NSAIDs, 
dihydroergotamine (up to 3 days per week) or ergot derivatives
(except methergine)
Octreotide
Opioids are allowed with restrictions, maximum 2 days per week
Transitional treatment
Disallowed for 30 days prior to the Screening Period 2 and until the end 
of Week 4: 
Greater occipital nerve (GON) block 
Injected and oral corticosteroids 
Preventive treatment:
Stable dose for one month prior to Screening visit 2 and until the end of 
Week 4: 
Verapamil maximum dose 240 mg/day
Topiramate maximum dose 50 mg/day
Gabapentin maximum dose 1200 mg/day
Valproate maximum dose 900 mg/day
Candesartan maximum dose 16 mg/day
Lithium maximum dose 12 mmol/day and/or se-lithium less than 
0.6 mmol/l
Allowed at any time with a restriction on the dose:
Melatonin maximum dose 9 mg/day
Other medicines used as preventive treatment for CH are disallowed for 
one month prior to Screening visit 2 and until the Safety Follow-Up 
Visit
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704


H. Lundbeck A/S
Confidential
Study 19386A – Clinical Study Protocol
Page 112 of 112
Drug Class
Details
Other treatment and interventions:
Disallowed for 4 months prior to the Screening Period 2 and until the 
Safety Follow-Up Visit:
Botulinum toxin type A or B, that was administered in the head or 
neck area for treatment of cluster headache or other disorders, or for 
cosmetic use.
Disallowed for 30 days prior to the Screening Period 2 and until the 
Safety Follow-Up Visit:
indomethacin
any other cranial or extracranial nerve block 
any neuromodulation treatment
Gamma knife or other invasive procedures
Anti CGRP therapies
Anti-CGRP therapies are disallowed for ≤5 half-lives for mAbs and 
≤1 month for gepants prior to Screening Visit 2
Antihypertensives 
Candesartan and Verapamil allowed with restrictions- see Cluster 
Headache Therapies
Other medications in the same class are allowed 
Anti-impotence agents
Allowed if the dose has been stable for at least 12 weeks prior to the 
Screening Period 2 and remains stable until the Completion Visit
(Week 16)
Cannabinoids
Restrictive use (as per investigator judgement) of cannabinoids is 
allowed* 
COVID-19 vaccine
If possible, COVID -19 vaccine should not be administered within 1 
week prior to Screening Visit 2 and until the Primary Outcome Visit 
(Week 2).
If possible, COVID-19 vaccine should not be administered within ±3 
days of the second IMP infusion at Week 4.
Ergot alkaloids 
Methergine is disallowed for 14 days prior to the Screening Period 2 
and until the Safety Follow-Up Visit
Dihydroergotamine allowed as abortive treatment for up to 3 days per 
week
Other medications in the same class are allowed 
Steroids:
Oral and Systemic
Allowed with restrictions:
For transitional treatment for CH, see Cluster Headache Therapies
For indications other than cluster headache: 
-
Disallowed for 30 days prior to Screening Visit 2 and until end 
of Week 4
-
Short-term treatment (maximum 3 days, followed by potential 
tapering) is allowed from end of Week 4 until the SFU Visit  
Illicit substances
Disallowed for 2 months prior to the Screening Period 1 until the 
Safety Follow-Up Visit: Psilocybin (mushrooms), LSD, or 2-bromo-
LSD, or other illegal drugs. Restrictive use of cannabinoids is 
allowed, please see “Cannabinoids”
* The eligibility of patients who occasionally use cannabinoids (confirmed by either anamnesis or finding at 
Urine drug screen at Screening Visit 2) must be based on a confirmation from the investigator that the patient 
does not meet Exclusion criteria 10, 24 and 25.
LU Study Number: 
Pluto ID: 
Status:  
Version: 
19386A
Final
2.0
CLI_02068704

SAP_001.pdf: 
+ /XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Statistical Analysis Plan
Interventional, randomized, double-blind, parallel-group, 
placebo-controlled delayed-start study to evaluate the efficacy and 
safety of eptinezumab in patients with episodic Cluster Headache
Eptinezumab
6WXG\1R
$
6SRQVRU
+ /XQGEHFN $6/XQGEHFN
9DOE\&RSHQKDJHQ'HQPDUN
'DWHRIHGLWLRQ
2FWREHU
(GLWLRQKLVWRU\
(GLWLRQ0D\
(GLWLRQ2FWREHU
7KLVGRFXPHQWLVWKHSURSHUW\RI+/XQGEHFN$6DQG+/XQGEHFN$6LVWKHKROGHURIDQ\DQGDOO
UHODWHGLQWHOOHFWXDOSURSHUW\ULJKWVLQFOXGLQJEXWQRWOLPLWHGWRFRS\ULJKWV7KLVGRFXPHQWLV
FRQILGHQWLDO,WLVQRWWREHFRSLHGRUGLVWULEXWHGWRRWKHUSDUWLHVZLWKRXWSULRUZULWWHQDXWKRUL]DWLRQ
IURP+ /XQGEHFN $6
33'
33'
Y 
&/,B
1&7


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Table of Contents
List of Panels and Tables...............................................................................................................6
List of Abbreviations and Definitions of Terms ..........................................................................7
1
Objectives...............................................................................................................................8

3ULPDU\2EMHFWLYH

6HFRQGDU\2EMHFWLYHV 

6DIHW\2EMHFWLYH
2
Study Design...........................................................................................................................8
3
Definitions ............................................................................................................................11

'HILQLWLRQRI%DVHOLQH

'HILQLWLRQRI3HULRGV

'HILQLWLRQRI:LWKGUDZDO

'HILQLWLRQRI3ODQQHGYHUVXV$FWXDO7UHDWPHQW 
4
COVID-19 ............................................................................................................................14
5
Endpoints..............................................................................................................................14

3ULPDU\(QGSRLQW

.H\6HFRQGDU\(QGSRLQWV

6HFRQGDU\(QGSRLQWV 

([SORUDWRU\(QGSRLQWV

6DIHW\(QGSRLQWV
6
Analysis Sets.........................................................................................................................16
7
Descriptive Statistics ...........................................................................................................17
8
Patient Disposition...............................................................................................................18

6XPPDU\RI3DWLHQW'LVSRVLWLRQ

:LWKGUDZDOV
9
Demographics and Baseline Characteristics.....................................................................19
10
Recent and Concomitant Medication ................................................................................19
11
Exposure...............................................................................................................................20
12
eDiary Compliance ..............................................................................................................21
13
Efficacy.................................................................................................................................21

*HQHUDO(IILFDF\$QDO\VLV0HWKRGRORJ\

7HVWLQJ6WUDWHJ\

$QDO\VLV0HWKRGRORJ\IRUWKH3ULPDU\(QGSRLQW

3ULPDU\(VWLPDQG

5DWLRQDOHIRUWKH3ULPDU\(VWLPDQG 

3ULPDU\$QDO\VLV

5DWLRQDOHIRU6HOHFWHG$QDO\VLV0HWKRGIRUWKH3ULPDU\(QGSRLQW

6HQVLWLYLW\$QDO\VHVRIWKH3ULPDU\(QGSRLQW 

6HQVLWLYLW\$QDO\VHVWRDVVHVVWKHLPSDFWRIPLVVLQJREVHUYDWLRQV

Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI

6HQVLWLYLW\DQDO\VLVWRDVVHVVWKHLPSDFWRIXVHRIWUDQVLWLRQDO
PHGLFDWLRQIRUH&+

$QDO\VLV0HWKRGRORJ\IRUWKH.H\6HFRQGDU\(QGSRLQWV

$QDO\VLVRIWKH.H\6HFRQGDU\(QGSRLQWV

&RQWLQXRXVHQGSRLQWV 

5HVSRQVHUHGXFWLRQIURP%DVHOLQHLQWKHQXPEHURI
ZHHNO\DWWDFNV:HHNV

7LPHIURPILUVWLQIXVLRQRI,03WRUHVROXWLRQRIFOXVWHUKHDGDFKH
ERXWZLWKLQWKHILUVWZHHNV 

5DWLRQDOHIRU6HOHFWHG$QDO\VLV0HWKRGIRUWKH.H\6HFRQGDU\(QGSRLQWV


6HQVLWLYLW\$QDO\VHVRIWKH.H\6HFRQGDU\(QGSRLQWV 

$QDO\VLVRIWKH6HFRQGDU\(QGSRLQWV

$QDO\VLVRIWKH([SORUDWRU\(QGSRLQWV

&RYDULDWH,QYHVWLJDWLRQDQG6XEJURXS$QDO\VHV
14
Safety ....................................................................................................................................32

$GYHUVH(YHQWV

*HQHUDO0HWKRGRORJ\IRU$GYHUVH(YHQWV

&RGLQJRI$GYHUVH(YHQWV

&ODVVLILFDWLRQRI$GYHUVH(YHQWV 

$OORFDWLRQRI7($(VWR7UHDWPHQW3HULRGV

3UHVHQWDWLRQRI$GYHUVH(YHQWV

3UHVHQWDWLRQRI3UHWUHDWPHQW$GYHUVH(YHQWV

3UHVHQWDWLRQRI7UHDWPHQWHPHUJHQW$GYHUVH(YHQWV 

3UHVHQWDWLRQRI'HDWKV

3UHVHQWDWLRQRI6HULRXV$GYHUVH(YHQWV

3UHVHQWDWLRQRI$GYHUVH(YHQWV/HDGLQJWR:LWKGUDZDO

3UHVHQWDWLRQRI$GYHUVH(YHQWV/HDGLQJWR6WXG\'UXJ,QIXVLRQ
,QWHUUXSWLRQ

3UHVHQWDWLRQRI$GYHUVH(YHQWVRI6SHFLDO,QWHUHVW

*HQHUDO0HWKRGRORJ\IRU2WKHU6DIHW\'DWD

&OLQLFDO6DIHW\/DERUDWRU\7HVW'DWD 

'DWD3UHVHQWDWLRQ

3RWHQWLDO'UXJLQGXFHG/LYHU,QMXU\',/,

9LWDO6LJQVDQG:HLJKW

(&*V

2WKHU6DIHW\(QGSRLQWV

&ROXPELD6XLFLGH6HYHULW\5DWLQJ6FDOH&66566FRUHV
15
Immunogenicity ...................................................................................................................39
16
Pharmacokinetic/Pharmacodynamic Analyses.................................................................39
17
Blinded Data Reviews..........................................................................................................39
18
Interim Analyses..................................................................................................................40
19
Sample Size Considerations................................................................................................40
20
Statistical Software..............................................................................................................41
21
Changes to Analyses Specified in the Protocol..................................................................41
22
Changes compared to version 1 of the SAP.......................................................................41
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
23
Details on Data Handling....................................................................................................42

'HULYHG9DULDEOHV 

H'LDU\

,PSXWDWLRQRIPLVVLQJEDVHOLQHDVVHVVPHQWV

,PSXWDWLRQRIPLVVLQJSRVWEDVHOLQHH'LDU\DVVHVVPHQWV

,PSXWDWLRQIRUVHQVLWLYLW\DQDO\VLVDVVHVVLQJWKHLPSDFWRIXVHRI
WUDQVLWLRQDOPHGLFDWLRQIRUH&+

5HVSRQGHU5DWHV 

7LPHIURPILUVWLQIXVLRQRIHSWLQH]XPDEWRUHVROXWLRQRIFOXVWHU
KHDGDFKHERXWZLWKLQWKHILUVWZHHNVDQGZHHNV

3DWLHQW*OREDO,PSUHVVLRQRI&KDQJH3*,&

6OHHS,PSDFW6FDOH6,6

(XURTRO'LPHQVLRQ± /HYHOV(4'/

+HDOWK&DUH5HVRXUFH8WLOL]DWLRQ+&58

:RUN3URGXFWLYLW\DQG$FWLYLW\,PSDLUPHQW*HQHUDO+HDOWKYHUVLRQ
:3$,*+

$VVLJQLQJ'DWDWR9LVLWV 

5DWLQJ6FDOHV

H'LDU\

6DIHW\9DULDEOHV 

+DQGOLQJ0LVVLQJRU,QFRPSOHWH'DWHV7LPHV 

:LWKGUDZDO 'DWH 

,036WDUWDQG6WRSWLPHSRLQWV 

0HGLFDO'LVRUGHU6WDUWDQG6WRS'DWHV 

0HGLFDWLRQ6WDUWDQG6WRS'DWHV

$GYHUVH(YHQW6WDUWDQG6WRS'DWHV

7UHDWPHQWHPHUJHQW$(V

'DWDZLWK0XOWLSOH5HFRUGV

'RVH&KDQJHVLQ0HGLFDWLRQ(YHQWV

&KDQJHVLQ,QWHQVLW\RU6HULRXVQHVVRI$GYHUVH(YHQWV 
References .....................................................................................................................................53
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Appendices
$SSHQGL[,
6WDWLVWLFDO $QDO\VLV 3ODQ$XWKHQWLFDWLRQ DQG $XWKRUL]DWLRQ 
$SSHQGL[,,
6$6 &RGH
$SSHQGL[,,,
3&6&ULWHULD 
$SSHQGL[,9
6WXG\IORZFKDUW
$SSHQGL[9
$GYHUVH(YHQWVRI6SHFLDO,QWHUHVW 
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
List of Panels and Tables
3DQHO 
6WXG\'HVLJQ 
3DQHO
&66566FRUHV  
3DQHO
&KDQJHVWRWKH6$3IURP(GLWLRQWR 
3DQHO
'HULYDWLRQRI:3$,*+VXEVFRUHV 
3DQHO
:LQGRZLQJUXOHVIRUVFDOHV 
3DQHO
:LQGRZLQJUXOHVIRU/DEDQG(&*DVVHVVPHQWV 
3DQHO
:LQGRZLQJUXOHVIRU96ERG\DVVHVVPHQWV 
7DEOH
3&6&ULWHULDIRU&OLQLFDO6DIHW\/DERUDWRU\7HVWV  
7DEOH
3&6&ULWHULDIRU9LWDO6LJQV:HLJKW%0,DQG:DLVW&LUFXPIHUHQFH  
7DEOH
3&6&ULWHULDIRU(&*3DUDPHWHUV 
7DEOH
6WXG\3URFHGXUHVDQG$VVHVVPHQWV 
7DEOH
$GYHUVH(YHQWVRI6SHFLDO,QWHUHVW 
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
List of Abbreviations and Definitions of Terms
$(6,
DGYHUVHHYHQWVRIVSHFLDOLQWHUHVW
$1&29$
DQDO\VLVRIFRYDULDQFH
$356
DOOSDWLHQWVUDQGRPL]HGVHW
$376
DOOSDWLHQWVWUHDWHGVHW
$376B'6
DOOSDWLHQWVWUHDWHGLQ'HOD\HG6WDUW3HULRGVHW
$376B,1
DOOSDWLHQWVWUHDWHGDWLQWHULPVHW
$7&
DQDWRPLFDOWKHUDSHXWLFFKHPLFDO
&,
FRQILGHQFHLQWHUYDO
',/,
GUXJLQGXFHGOLYHULQMXU\
H&+
(SLVRGLF&OXVWHU+HDGDFKH
,03
LQYHVWLJDWLRQDOPHGLFLQDOSURGXFW
0&0&
0RQWH&DUOR0DUNRY&KDLQ
0HG'5$
0HGLFDO'LFWLRQDU\IRU5HJXODWRU\$FWLYLWLHV
0050
PL[HGPRGHOIRUUHSHDWHGPHDVXUHPHQWV
01$5
PLVVLQJQRWDWUDQGRP
3&6
SRWHQWLDOO\FOLQLFDOO\VLJQLILFDQW
S0,
SODFHEREDVHGPXOWLSOHLPSXWDWLRQ
6$(
VHULRXVDGYHUVHHYHQW
6$6
VWDWLVWLFDOVRIWZDUHSDFNDJHIURPWKH6$6 ,QVWLWXWH
6'
VWDQGDUGGHYLDWLRQ
62&
V\VWHPRUJDQFODVV
7($(
WUHDWPHQWHPHUJHQWDGYHUVHHYHQW
:+2''
:RUOG+HDOWK2UJDQL]DWLRQ'UXJ'LFWLRQDU\
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
1
Objectives
1.1
Primary Objective
7RHYDOXDWHWKHHIILFDF\RIHSWLQH]XPDELQSDWLHQWVZLWKH&+
1.2
Secondary Objectives
7RHYDOXDWHWKHHIILFDF\RIHSWLQH]XPDE RQKHDOWKUHODWHGTXDOLW\RIOLIHKHDOWKFDUHUHVRXUFH
XWLOL]DWLRQDQGZRUNSURGXFWLYLW\
1.3
Safety Objective
7RHYDOXDWHWKHVDIHW\DQGWROHUDELOLW\RIHSWLQH]XPDE
2
Study Design
7KLVLVDQLQWHUYHQWLRQDOPXOWLUHJLRQDOUDQGRPL]HGGRXEOHEOLQGSODFHERFRQWUROOHG
GHOD\HGVWDUWVWXG\GHVLJQHGWRGHPRQVWUDWHWKHHIILFDF\DQGVDIHW\RIHSWLQH]XPDELQ
SDWLHQWVZLWKHSLVRGLF&OXVWHU+HDGDFKHH&+
$QRYHUYLHZRIWKHVWXG\LVSUHVHQWHGLQ 3DQHO  DQGWKHVFKHGXOHGVWXG\SURFHGXUHVDQG
DVVHVVPHQWVDUHVXPPDUL]HGLQ $SSHQGL[,9
7KHWDUJHWSRSXODWLRQIRUWKLVVWXG\LVGHILQHGDVSDWLHQWVZLWKH&+EDVHGRQWKH,+6,&+'
FODVVLILFDWLRQZLWKDGRFXPHQWHGKLVWRU\RIH&+RIDWOHDVWPRQWKVSULRUWR6FUHHQLQJ9LVLW
ZLWKDPHGLFDOKLVWRU\RIILUVWV\PSWRPVRIFOXVWHUKHDGDFKHIURP \HDUVRIDJHZLWKD
SULRUKLVWRU\RIFOXVWHUERXWVODVWLQJZHHNVRUORQJHU ZKHQXQWUHDWHGZLWKPLQLPXPRIDW
OHDVWWRWDOFOXVWHUKHDGDFKHDWWDFNVRXWRIWKHGD\6FUHHQLQJ3HULRGDQGDPD[LPXPRI
FOXVWHUKHDGDFKHDWWDFNVRXWRIWKHGD\6FUHHQLQJ3HULRGKDVGHPRQVWUDWHGFRPSOLDQFH
ZLWKWKHH'LDU\E\HQWU\RIGDWDIRUDWOHDVWRI WKHGD\VRI6FUHHQLQJ3HULRGDQGLVDJHG
DQG\HDUVDW6FUHHQLQJ9LVLW
$WWKHEHJLQQLQJRIWKHZHHN3ODFHERFRQWUROOHG3HULRGILUVWSDUWSDWLHQWVUHFHLYH
HSWLQH]XPDE PJRUSODFHERDFFRUGLQJWRWKHUDQGRPL]DWLRQ,QIXVLRQ  LQDUDWLR$W
WKHEHJLQQLQJRIWKHVHFRQGSDUWRIWKHVWXG\VWDUWLQJZLWK,QIXVLRQ SDWLHQWVWKDWUHFHLYHG
SODFHER DW,QIXVLRQ LQWKHVWXG\ZLOOUHFHLYHHSWLQH]XPDEPJ$WWKHEHJLQQLQJRIWKH
VHFRQGSDUWRIWKHVWXG\VWDUWLQJZLWK,QIXVLRQ SDWLHQWVWKDWUHFHLYHGHSWLQH]XPDEPJ
DW,QIXVLRQLQWKHVWXG\ZLOOUHFHLYHSODFHEREXWZLOOFRQWLQXHWREHH[SRVHGWRHSWLQH]XPDE
IROORZLQJWKHZHHN3ODFHERFRQWUROOHG3HULRGGXHWRWKHORQJKDOIOLIHRIHSWLQH]XPDEWKH
H[SRVXUHRIHSWLQH]XPDELVLOOXVWUDWHGLQ3DQHO 
3DWLHQWVZLOOHQWHU6FUHHQLQJ3HULRGDIWHU6FUHHQLQJ9LVLW7KHSDWLHQWVFDQWUDQVLWLRQIURP
6FUHHQLQJ3HULRGWR6FUHHQLQJ3HULRGDWDQ\WLPHGXULQJWKHILUVWZHHNVDVVRRQDV
WKH\H[SHULHQFHWKHEHJLQQLQJRIDFOXVWHUKHDGDFKHERXWZKLFKLVFKDUDFWHUL]HGE\WKH
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
SUHVHQFHRIDWOHDVWRQHW\SLFDOFOXVWHUKHDGDFKHDWWDFNDQGQRWODWHUWKDQZHHNDIWHUWKH
VWDUWRIWKHILUVWDWWDFN )RUSDWLHQWVZKRHQWHUWKHVWXG\DOUHDG\LQFOXVWHUKHDGDFKHERXW
6FUHHQLQJ9LVLWDQG6FUHHQLQJ9LVLWFDQEHFRPELQHGWRFDSWXUHDOODVVHVVPHQWVIRU
6FUHHQLQJ9LVLWDQG6FUHHQLQJ9LVLWRQWKHVDPHGD\
8QGHUH[FHSWLRQDOFLUFXPVWDQFHVZKHQDSDWLHQWLVDEOHWRDWWHQG6FUHHQLQJ9LVLWRQO\
GXULQJWKHVHFRQGZHHNDIWHUWKHILUVWW\SLFDOFOXVWHUKHDGDFKHDWWDFNWKHSRVVLELOLW\WRHQURO
WKLVSDWLHQWLQWKHVWXG\ZLOOEHGLVFXVVHGZLWKWKHLQYHVWLJDWRUDQGWKHGHFLVLRQ RQZKHWKHUWR
HQUROWKHSDWLHQWZLOOEHWDNHQLQWKHFRQWH[WRINQRZQKLVWRU\RIW\SLFDOGXUDWLRQRIWKHERXW
IRUWKHLQGLYLGXDOSDWLHQW
5HVFUHHQLQJRISDWLHQWV ZLOOEHDOORZHGIRUSDWLHQWVZKRGRQRWPHHWSUHGHILQHGVSHFLILF
HOLJLELOLW\FULWHULDGHWDLOVDUHSUHVHQWHGLQWKHVWXG\SURWRFRO
(OLJLEOHSDWLHQWVZLOOEHUDQGRPO\DVVLJQHGWRUHFHLYHEOLQGHGWUHDWPHQWDWWKH%DVHOLQH9LVLW
'D\9LVLWZLWKHLWKHUHSWLQH]XPDEPJRUSODFHERDGPLQLVWHUHGDVDQ,9LQIXVLRQ
RYHUPLQXWHVPLQXWHV3UHIHUDEO\WKHLQIXVLRQVKRXOGEHDGPLQLVWHUHGLQWKH
PRUQLQJ
$OOSDWLHQWVZLOOFRQWLQXHLQWKH$FWLYH7UHDWPHQW3HULRGRIWKHVWXG\DQGZLOOUHFHLYHD
VHFRQG,03LQIXVLRQHSWLQH]XPDEPJRUSODFHERDGPLQLVWHUHGRYHU PLQXWHV
PLQXWHVDWWKHHQGRI:HHN9LVLWLQDEOLQGHGPDQQHUVRWKDWSDWLHQWVSUHYLRXVO\
H[SRVHGWRHSWLQH]XPDEZLOOUHFHLYHSODFHERDQGSDWLHQWVUDQGRPL]HGWRSODFHERZLOOUHFHLYH
HSWLQH]XPDEPJ
7KH6DIHW\)ROORZXS9LVLWZLOOWDNHSODFHDW:HHN9LVLWZHHNVKDOIOLYHVDIWHU
WKHVHFRQG,03DGPLQLVWUDWLRQ
7KHWRWDOVWXG\GXUDWLRQIURP6FUHHQLQJ9LVLWWRWKH6DIHW\)ROORZXS9LVLWLVXSWR
ZHHNVDQGLQFOXGHV6FUHHQLQJ3HULRGXSWRPRQWKVZHHNV6FUHHQLQJ3HULRG
GD\VD3ODFHERFRQWUROOHG3HULRGZHHNVDQ$FWLYH7UHDWPHQW3HULRGZHHNVD3RVW
WUHDWPHQW2EVHUYDWLRQDO3HULRGZHHNVDQGD6DIHW\)ROORZXS3HULRGZHHNV
3DWLHQWVZKRZLWKGUDZIURPWKHVWXG\H[FHSWIRUWKRVHZKRZLWKGUDZWKHLUFRQVHQWZLOOEH
DVNHGWRDWWHQGD:LWKGUDZDO9LVLWDVVRRQDVSRVVLEOHDQGDIXUWKHU6DIHW\)ROORZ8S9LVLW
6)8VFKHGXOHGZHHNVDIWHUWKHODVW,03DGPLQLVWUDWLRQ
3DWLHQWVDUHDOORZHGWRZLWKGUDZIURPWUHDWPHQWDQGLQWKLVZD\QRWJHWWKHVHFRQG LQIXVLRQ
ZKLOHVWD\LQJ LQWKHVWXG\7KHDVVHVVPHQWIURPWKHVHSDWLHQWVZLOOEHKDQGOHGDFFRUGLQJWR
VHFWLRQ
7KHIROORZLQJYLVLWVZLOOEHVLWHYLVLWV6FUHHQLQJ9LVLW6FUHHQLQJ9LVLW%DVHOLQH9LVLW
)LUVW9LVLWRIWKH3ODFHERFRQWUROOHG3HULRG'D\9LVLWUDQGRPL]DWLRQDQG,03
LQIXVLRQ/DVW9LVLWRIWKH3ODFHERFRQWUROOHG3HULRGDWWKHHQGRI:HHN9LVLW VHFRQG
,03LQIXVLRQ&RPSOHWLRQ9LVLWDW:HHN9LVLWDQG6)8YLVLWDW:HHN9LVLWRU
:LWKGUDZDO9LVLWLIDSSOLFDEOH
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
$OORWKHUVWXG\YLVLWVZLOOEHSKRQHFRQWDFWYLVLWV
,QH[FHSWLRQDOVLWXDWLRQV VXFKDVZKHUH&29,'SDQGHPLFUHVWULFWLRQVLPSDFWWKHDELOLW\WR
SHUIRUPVLWHYLVLWVVLWHYLVLWVPD\RQO\FRQVLVWRIEORRGVDPSOLQJDQGXULQHVDPSOLQJIRU
FOLQLFDOODERUDWRU\WHVWVH[SORUDWRU\HSWLQH]XPDETXDQWLILFDWLRQ$'$LQFOXGLQJ1DEDQG
H[SORUDWRU\ELRPDUNHUV(&*YLWDOVLJQVSK\VLFDODQGQHXURORJLFDOH[DPLQDWLRQVDGYHUVH
HYHQWUHFRUGLQJDQG,03DGPLQLVWUDWLRQZKLOHWKHUHPDLQLQJDVVHVVPHQWVH'LDU\H352V
&6656DQGLQYHVWLJDWRUHYDOXDWLRQVFDQEHFRQGXFWHGUHPRWHO\YLDDYLUWXDOFOLQLFYLVLW
7KHVHFDVHVPXVWEHDSSURYHGE\WKH&52¶VPHGLFDOPRQLWRU
3DWLHQWVZLOOEHDVVLJQHGDQH'LDU\DWWKH6FUHHQLQJ9LVLWDQGZLOOEHUHTXLUHGWRFRPSOHWH
WKLVGDLO\IURPWKHWLPHRI6FUHHQLQJ9LVLWXQWLOWKH&RPSOHWLRQ9LVLW:HHN9LVLWRU
XQWLOWKH:LWKGUDZDO9LVLW
'XULQJWKHVWXG\YLVLWVZLWK,03LQIXVLRQ9LWDO6LJQV ZLOOEHSHUIRUPHGEHIRUHDQGDIWHUWKH
LQIXVLRQ$WWKHVHYLVLWV$(VDVZHOODVVDIHW\ODERUDWRU\WHVWV(&*ZHLJKWDQGYLWDOVLJQV
LQFOXGLQJERG\WHPSHUDWXUHZLOODOVREH FROOHFWHG(OHFWURQLFSDWLHQWUHSRUWHGRXWFRPHV
H352VPXVWEHFRPSOHWHGSULRUWRLQIXVLRQ
$QLQWHULPDQDO\VLVZLOOEHFRQGXFWHGIRUIXWLOLW\VHHFKDSWHU 
,Q WKHFKDUWHUIRUWKHLQWHULPDQDO\VLVLWLVGHVFULEHGWKDWLQFDVHLWZDVGHFLGHGWRVWRS
UHFUXLWPHQWEDVHGRQWKHUHVXOWRIWKHLQWHULPDQDO\VLVQRIXUWKHUSDWLHQWVZRXOGEHWUHDWHG
ZLWK,033DWLHQWVWKDWKDGUHFHLYHGWKHILUVW,03LQIXVLRQEXWQRWWKH VHFRQGDWWKHWLPH
ZKHUHLWZDVGHFLGHGWRHQGUHFUXLWPHQWZRXOGQRWEHJLYHQDVHFRQGLQIXVLRQDQGZRXOGEH
IROORZHGIRUZHHNVDIWHUWKH,03LQIXVLRQLQVWHDGRIZHHNV7KHVHSDWLHQWVZLOODWWHQG
WKH:HHN9LVLWDVSODQQHGEXWVNLSWKH:HHN9LVLWDVVHVVPHQWVDQGKDYHWKH:HHN
9LVLWSURFHGXUHVDW:HHNDQGWKH6)8YLVLWDW:HHN
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Panel 1
Study Design
,QWKH3ODFHERFRQWUROOHG3HULRGILUVWSDUWSDWLHQWVUHFHLYHHSWLQH]XPDE PJRUSODFHERDFFRUGLQJWRWKHUDQGRPL]DWLRQ
,QIXVLRQ ,QWKHVHFRQGSDUWRIWKHVWXG\VWDUWLQJZLWK,QIXVLRQ WKHSDWLHQWVZKRUHFHLYHGHSWLQH]XPDE PJDW
,QIXVLRQ FRQWLQXHWREHH[SRVHGWRHSWLQH]XPDEEXWIRUEOLQGLQJSXUSRVHVWKH\UHFHLYHDQLQIXVLRQZLWKSODFHER
,QIXVLRQ ZKLOHWKHSDWLHQWVWKDWUHFHLYHGSODFHERDW,QIXVLRQ UHFHLYHHSWLQH]XPDEDW,QIXVLRQ 7KHEOXHEDUVUHSUHVHQW
WKHWRWDOZHHNELRDYDLODELOLW\RIHSWLQH]XPDELQWKHWZR JURXSV
3
Definitions
3.1
Definition of Baseline
8QOHVVRWKHUZLVHVSHFLILHGWKHEDVHOLQHYDOXHLVWKHYDOXHFDSWXUHGHLWKHUGXULQJ WKH
6FUHHQLQJ3HULRG9LVLWRUDWWKH%DVHOLQH9LVLW SULRUWRWKHLQIXVLRQZKLFKHYHULVODWHU
)RUWKHHIILFDF\HQGSRLQWVEDVHGRQWKHH'LDU\WKHGDWDFROOHFWHGZLWKLQWKHILUVWGD\VRI
6FUHHQLQJ3HULRGWKHEDVHOLQHSHULRGZLOOEHXVHGWRFDOFXODWHWKHEDVHOLQHQXPEHURI
ZHHNO\HYHQWVIRUWKHHQGSRLQWV ,QFDVHRIDQ H[WHQVLRQRIWKH6FUHHQLQJ3HULRGWKH
EDVHOLQHQXPEHURIZHHNO\HYHQWVZLOOEHFDOFXODWHGEDVHGRQWKHILUVWGD\VRIWKHH[WHQGHG
SHULRGLHGD\
6HHFKDSWHU  IRUKDQGOLQJRIPLVVLQJGDWD
3.2
Definition of Periods
7KHVWXG\FRQVLVWVRIWKHIROORZLQJSHULRGV

Screening Period 1 GD\WRPRQWKVZHHNV6WDUWVDWWKH9LVLWDQGFRQWLQXHVXS
WREXWQRWLQFOXGLQJ9LVLW
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI

Screening Period 2 GD\V6WDUWVDW9LVLWDQGFRQWLQXHVXSWREXWQRWLQFOXGLQJ9LVLW

Placebo-controlled Period ZHHNV6WDUWVDW9LVLW,03LQIXVLRQDQGFRQWLQXHVXSWR
VWDUWRI 9LVLW QG ,03LQIXVLRQ

Active Treatment Period ZHHNV6WDUWVDW QG ,03LQIXVLRQDQGFRQWLQXHVXSWREXWQRW
LQFOXGLQJ9LVLW

Post-treatment Observational Period ZHHNV6WDUWVDW 9LVLWDQGFRQWLQXHVXSWREXW
QRWLQFOXGLQJ9LVLW

Safety Follow-up Period ZHHNV6WDUWVDW9LVLWDQGFRQWLQXHVXSWRDQGLQFOXGLQJ
9LVLW
8QOHVVRWKHUZLVHVSHFLILHGWKH$FWLYH7UHDWPHQW3HULRGWKH3RVWWUHDWPHQWREVHUYDWLRQDO
3HULRGDQGWKH6DIHW\)ROORZXS3HULRG ZLOOEHUHSRUWHGDVRQHSHULRGFDOOHGWKHDelayed 
Start Period
)RUSDWLHQWVWKDWZHUHLQWKH3ODFHERFRQWUROOHGSHULRGZKHQWKHUHFUXLWPHQWZDVVWRSSHGIRU
IXWLOLW\WKH\DUHFRQVLGHUHGWREHLQWKH'HOD\HG6WDUW3HULRGIURPWKHWLPHRIWKHLU:HHN
9LVLW,QJHQHUDOWKHWHUPtreatment ZLOOEHXQGHUVWRRGDVWKHtreatment sequence LIWKHSHULRG
LQVFRSHDOVRFRYHUVSDUWVRIWKH'HOD\HG6WDUW3HULRG
7KHGHILQLWLRQVRIWKHVHSHULRGVZLOOLQVRPHFDVHVGLIIHUIURPWKHGHVFULSWLRQDERYH
GHSHQGLQJRQZKHWKHUWKHDVVHVVPHQWVDUHHIILFDF\RUVDIHW\DVVHVVPHQWV6HHIXUWKHU
GHVFULSWLRQVLQFKDSWHU  IRUWKLV
3.3
Definition of Withdrawal
$Q\ZLWKGUDZDOVIURPWUHDWPHQWDIWHUUDQGRPLVDWLRQEXWSULRUWRWKHILUVWLQIXVLRQ ZLOOEH
FDSWXUHG DVZLWKGUDZDOLQWKH3%2FRQWUROOHG3HULRGLQFOXGLQJWKHUHDVRQIRUZLWKGUDZDO
IURPWUHDWPHQW
$IWHUUHFHLYLQJWKHILUVWLQIXVLRQSDWLHQWVFRXOGZLWKGUDZIURPWUHDWPHQWDQGLQWKLVZD\QRW
UHFHLYH WKHVHFRQGLQIXVLRQ'XHWRWKHH[SHFWHGORQJGXUDWLRQRIWKHWUHDWPHQWHIIHFWDIWHUWKH
ILUVWLQIXVLRQWKLVZLOOEHFRQVLGHUHGWRRQO\DIIHFWWKHWUHDWPHQWUHFHLYHGLQWKH'HOD\HG6WDUW
3HULRGDQGWKXVLWZDVQRWFRQVLGHUHGSRVVLEOHIRUSDWLHQWVWRZLWKGUDZIURPWUHDWPHQWIRUWKH
3ODFHERFRQWUROOHG3HULRGDOWKRXJKSDWLHQWVFRXOGZLWKGUDZIURPVWXG\GXULQJWKLVSHULRG
,IDSDWLHQWLVZLWKGUDZQIURPWKHVWXG\DQG GRHVQRWKDYHDVHFRQGLQIXVLRQWKHQWKH3%2
FRQWUROOHGSHULRGLVQRWFRPSOHWHG,IDSDWLHQWLVZLWKGUDZQIURPWKHVWXG\DQGKDVJRWWHQWKH
VHFRQGLQIXVLRQWKH3%2FRQWUROOHGSHULRGLVFRPSOHWHGEXWWKH'HOD\HGVWDUW3HULRG LVQRW
,IDSDWLHQWLVZLWKGUDZQIURPWUHDWPHQWDQG GRHVQRWKDYHDVHFRQGLQIXVLRQWKHQWKH3%2
FRQWUROOHG3HULRGLVRQO\FRPSOHWHGLIWKHSDWLHQWGLGQRWZLWKGUDZIURPVWXG\LQWKH3%2
FRQWUROOHG3HULRG
7KHJURXSRISDWLHQWVZLWKGUDZQIURPWUHDWPHQWSULRUWRUHFHLYLQJWKHVHFRQGLQIXVLRQZLOO
EHGHVFULEHGDVwithdrawn from treatment
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
7KHJURXSRISDWLHQWVZLWKGUDZQ IURPVWXG\GXULQJWKH3ODFHERFRQWUROOHG3HULRGZLOOEH
GHVFULEHGDVwithdrawn from study in the Placebo-controlled Period. 7KHJURXS RISDWLHQWV
WKDWUHFHLYHGERWKVW DQGQG LQIXVLRQDQGGLGQRWZLWKGUDZGXULQJWKH3ODFHERFRQWUROOHG
3HULRG ZLOOEHGHVFULEHGDVcompleted the Placebo-controlled Period
7KHJURXSRISDWLHQWVZLWKGUDZQ IURPVWXG\LQWKH'HOD\HG6WDUW 3HULRG ZLOOEHGHVFULEHGDV
withdrawn from study in the Delayed Start Period. 7KHJURXSRISDWLHQWVWKDWUHFHLYHGWKH
VHFRQGLQIXVLRQDQGGLGQRWZLWKGUDZIURPVWXG\ZLOOEHGHVFULEHGDVcompleted the Delayed 
Start Period
)RUSDWLHQWVWKDWZHUHLQWKH3ODFHER&RQWUROOHG3HULRGZKHQUHFUXLWPHQWZDVVWRSSHGWKH\
ZLOOEHGHVFULEHGDVcompleted the Placebo-controlled Period LIWKH\KDYHD:HHN9LVLW RU
HOVHWKH\ZLOOEHGHVFULEHGDVwithdrawn from study in the Placebo-controlled Period.,IWKH
SDWLHQWVKDGD:HHN9LVLWWKH\ZLOOEHGHVFULEHGDVwithdrawn from study in the Delayed 
Start Period LIWKH\ZHUHZLWKGUDZQRUDVcompleted the Delayed start PeriodLIWKH\ZHUH
QRWZLWKGUDZQLQWKH'HOD\HG6WDUW3HULRG
3.4
Definition of Planned versus Actual Treatment
$WEDVHOLQH SDWLHQWVZLOOUHFHLYHHLWKHUHSWLQH]XPDEPJ RUSODFHERLQWKH3ODFHER
FRQWUROOHG3HULRG$IWHUZHHNVRIWUHDWPHQWLQWKH3ODFHERFRQWUROOHGSHULRG SDWLHQWV
SUHYLRXVO\UDQGRPL]HG WRHSWLQH]XPDEZLOOUHFHLYHSODFHERDQGSDWLHQWVUDQGRPL]HGWR
SODFHERZLOOUHFHLYHHSWLQH]XPDE PJ LQWKH'HOD\HG6WDUW3HULRG
7KHWHUPWUHDWPHQWVHTXHQFHZLOOEHXVHGWRGHQRWHWKHWUHDWPHQWVDULVLQJE\FRPELQLQJWKH
WUHDWPHQWVUHFHLYHGLQWKH3ODFHERFRQWUROOHG3HULRGDQGWKHWUHDWPHQWVUHFHLYHGLQWKH
'HOD\HG6WDUW3HULRGSODFHERHSWLQH]XPDE PJ  HSWLQH]XPDE PJSODFHERLHLIDOO
SDWLHQWVUHFHLYHWKHLUWUHDWPHQWDVSODQQHGWKHQWKHJURXSVUHIOHFWLQJWKHIXOOWUHDWPHQW
UHFHLYHGDUHSODFHERHSWLQH]XPDE PJ DQGHSWLQH]XPDE PJ
3ODQQHGWUHDWPHQWLVGHILQHGDVWKHWUHDWPHQWDSDWLHQWZDVUDQGRPL]HGWR
$FWXDOWUHDWPHQWLVGHILQHGDVWKHWUHDWPHQWDSDWLHQWDFWXDOO\UHFHLYHGGXULQJWKHVWXG\,ID
SDWLHQWUHFHLYHGDGLIIHUHQW WUHDWPHQW WKDQZKDWZDVSODQQHGDWWKHILUVWLQIXVLRQWKHDFWXDO
WUHDWPHQWLQWKH3ODFHERFRQWUROOHG3HULRGZLOOHTXDOWKDW WUHDWPHQW)RUWKH'HOD\HG6WDUW
3HULRGLIDQ\SDWLHQWVE\PLVWDNHUHFHLYHHSWLQH]XPDE PJ  HSWLQH]XPDE PJ WKHLU
DFWXDOWUHDWPHQWZLOOEHFRQVLGHUHG DVHSWLQH]XPDE PJDQGLIDQ\SDWLHQWVE\PLVWDNH
UHFHLYHSODFHER  SODFHER WKHLUDFWXDOWUHDWPHQWZLOOEHFRQVLGHUHGDVSODFHERDOVRIRUWKH
'HOD\HG6WDUW3HULRG
)RUUHSRUWLQJSXUSRVHVWKHIROORZLQJZLOOEHVXPPDUL]HGE\SODQQHGWUHDWPHQW

(IILFDF\

'HPRJUDSKLFVDQGEDVHOLQHFKDUDFWHULVWLFV

'LVSRVLWLRQ

H'LDU\FRPSOLDQFH

&RQFRPLWDQWPHGLFDWLRQ
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
7RHQVXUHWKDWSDWLHQWVWKDWZHUHLQWKHSODFHERFRQWUROOHGSHULRGZKHQWKHUHFUXLWPHQWZDV
VWRSSHG DUHLQFOXGHGLQWKHWDEXODWLRQVDOVRWKHIROORZLQJFDWHJRULHVZLOOEHVXPPDUL]HGE\
SODQQHGWUHDWPHQW

$GYHUVHHYHQWV

([SRVXUH

6DIHW\ODERUDWRU\SDUDPHWHUVYLWDOVLJQV(&*DQG&6656
8QOHVVRWKHUZLVHVSHFLILHGGDWDOLVWLQJVZLOOGLVSOD\DFWXDOWUHDWPHQW
4
COVID-19
)RUWKLVVWXG\DOOSDWLHQWVDUHFRQVLGHUHGWRKDYHEHHQHQUROOHGDIWHUWKHEHJLQQLQJRIWKH
&29,'RXWEUHDN
7KHIROORZLQJLQIRUPDWLRQLVFROOHFWHGZLWKUHJDUGVWR&29,'

:KHWKHUDYLVLWZDVGRQHUHPRWHO\GXHWR&29,'LQFOXGLQJZKLFKDVVHVVPHQWV
ZHUHZHUHQRWSHUIRUPHG

:KHWKHUSDWLHQWVZLWKGUHZGXHWRWKH&29,'VLWXDWLRQ

:KHWKHUSDWLHQWVJRWGLDJQRVHGZLWK&29,'
6SHFLILFRXWSXWDGGUHVVLQJWKHLPSDFWRI&29,'IRUWKLVWULDOLVVSHFLILHGLQFKDSWHU 
5
Endpoints
5.1
Primary Endpoint
&KDQJHIURP%DVHOLQH LQ WKH QXPEHURIZHHNO\DWWDFNV:HHNV±
5.2
Key Secondary Endpoints

5HVSRQVHUHGXFWLRQIURP%DVHOLQHLQ WKHQXPEHURIZHHNO\DWWDFNV:HHNV

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\WLPHVDQDERUWLYHPHGLFDWLRQWULSWDQVRU
2ZDVXVHG :HHNV

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIGDLO\DWWDFNV'D\V

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\GD\V ZLWKDWWDFNVSHUGD\:HHNV

7LPHIURPILUVWLQIXVLRQRI,03WRUHVROXWLRQRIFOXVWHUKHDGDFKHERXWZLWKLQWKHILUVW
ZHHNV

1XPEHURIDWWDFNVVWDUWLQJ KRXUVDIWHUWKHVWDUWRIWKHILUVWLQIXVLRQ RI,03
5.3
Secondary Endpoints

&KDQJHIURP%DVHOLQHLQWKHGDLO\PHDQVFRUHRQSRLQWVHOIUDWLQJSDLQVHYHULW\VFDOH
'D\V
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV :HHN

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV :HHN

5HVSRQVHUHGXFWLRQ IURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV:HHN

5HVSRQVHUHGXFWLRQIURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV:HHN

5HVSRQVHUHGXFWLRQIURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV:HHNV

&KDQJHIURP%DVHOLQHLQWKHZHHNO\LQWHJUDWHGPHDVXUHRIIUHTXHQF\DQGLQWHQVLW\RISDLQ
:HHNV WKDWLVWKHVXPRI WKHLQWHQVLW\ZRUVWSDLQRQDSRLQWVHOIUDWLQJSDLQ
VHYHULW\VFDOHIRUHDFKDWWDFNGXULQJWKHZHHNV

&KDQJHIURP%DVHOLQHLQWKHZHHNO\LQWHJUDWHGPHDVXUHRIIUHTXHQF\DQGLQWHQVLW\RISDLQ
:HHNWKDWLVWKHVXPRI WKHLQWHQVLW\ZRUVWSDLQRQDSRLQWVHOIUDWLQJSDLQVHYHULW\
VFDOHIRUHDFKDWWDFNGXULQJWKDWZHHN

&KDQJHIURP%DVHOLQHLQWKHZHHNO\LQWHJUDWHGPHDVXUHRIIUHTXHQF\DQGLQWHQVLW\RISDLQ
:HHN WKDWLVWKHVXPRI WKHLQWHQVLW\ZRUVWSDLQRQDSRLQWVHOIUDWLQJSDLQVHYHULW\
VFDOHIRUHDFKDWWDFNGXULQJWKDWZHHN

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV:HHNV

&KDQJHIURP%DVHOLQHLQWKHZHHNO\LQWHJUDWHGPHDVXUHRIIUHTXHQF\DQGLQWHQVLW\RISDLQ
:HHNV WKDWLVWKHVXPRI WKHLQWHQVLW\ZRUVWSDLQRQDSRLQWVHOIUDWLQJSDLQ
VHYHULW\VFDOHIRUHDFKDWWDFNGXULQJWKHZHHNV

&KDQJHIURP%DVHOLQHLQWKHPHDQVFRUHRQ SRLQWVHOIUDWLQJSDLQVHYHULW\VFDOHDYHUDJH
SHUDWWDFNRYHUD ZHHNIRUHDFKRI:HHNV DQG

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNVIRUHDFKRI:HHNVDQG

3DWLHQW*OREDO,PSUHVVLRQRI&KDQJH3*,&VFRUHDWHDFKRI:HHNV DQG

&KDQJHIURP%DVHOLQHLQWKH6OHHS,PSDFW6FDOH6,6GRPDLQVFRUHV DWHDFKRI:HHNV
DQG

&KDQJHIURPEDVHOLQHLQ WKH (4'/ 9LVXDO$QDORJXH6FDOH9$6VFRUH DW:HHNV
DQG

+HDOWK&DUH5HVRXUFHV8WLOL]DWLRQ+&58DW%DVHOLQHDQG:HHN

&KDQJHIURP%DVHOLQHLQWKH:RUN3URGXFWLYLW\$FWLYLW\4XHVWLRQQDLUH*HQHUDO+HDOWK
VHFRQGYHUVLRQ:3$,*+VXEVFRUHV$EVHQWHHLVP3UHVHQWHHLVP:RUNSURGXFWLYLW\
ORVV$FWLYLW\LPSDLUPHQWDW:HHN
5.4
Exploratory Endpoints

5HVSRQVHUHGXFWLRQ IURP %DVHOLQH LQWKHQXPEHURIZHHNO\DWWDFNV:HHNV

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\WLPHVDQDERUWLYHPHGLFDWLRQWULSWDQVRU
2ZDVXVHG:HHNV

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\WLPHVDQDERUWLYHPHGLFDWLRQWULSWDQVRU
2ZDVXVHGIRUHDFKRIZHHNVDQG

7LPHIURPILUVWLQIXVLRQRIHSWLQH]XPDEWRUHVROXWLRQRIFOXVWHUKHDGDFKHERXWZLWKLQWKH
ILUVWZHHNVRQO\IRUSDWLHQWVUDQGRPL]HGWRHSWLQH]XPDEDW%DVHOLQH

8VH\HVQRRIDERUWLYHPHGLFDWLRQWULSWDQVRU 2IRUHDFKRI:HHNV WR 

8VH\HVQRRISUHYHQWLYHPHGLFDWLRQIRUHDFKRI:HHNV WR 
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI

8VH\HVQRRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVIRUHDFKRI:HHNV
WR 

1XPEHURIDWWDFNVVWDUWLQJ KRXUVRIWKHVWDUWRIWKHILUVWLQIXVLRQRI,03GLYLGHGLQWR
WKUHHSDUWVRQHIRUDWWDFNVVWDUWLQJ ! DQG  KRXUVDIWHUWKHVWDUWRIWKHILUVWLQIXVLRQRI
,03RQHIRUDWWDFNVVWDUWLQJ! DQG KRXUVDIWHUWKHVWDUWRIWKHILUVWLQIXVLRQ RI,03
DQGRQHIRUDWWDFNVVWDUWLQJ! DQG KRXUVDIWHUWKHVWDUWRIWKHILUVWLQIXVLRQRI,03

&KDQJHIURP%DVHOLQHLQWKH(4'/9LVXDO$QDORJXH6FDOH9$6VFRUHDW :HHNV
DQG 

3DWLHQW*OREDO,PSUHVVLRQRI&KDQJH3*,&VFRUHDW:HHNVDQG

1XPEHURIZHHNO\DWWDFNVIRUHDFKRI:HHNV WR 

6HYHULW\RISDLQDYHUDJHSHUDWWDFNRYHUDZHHNEDVHGRQD SRLQWVHOIUDWLQJSDLQ
VHYHULW\VFDOHIRUHDFKRI:HHNV WR 
5.5
Safety Endpoints

$GYHUVHHYHQWV

$EVROXWHYDOXHVDQGFKDQJHVIURP%DVHOLQHLQFOLQLFDOVDIHW\ODERUDWRU\WHVWYDOXHVYLWDO
VLJQVZHLJKWDQG(&*SDUDPHWHUYDOXHV

3RWHQWLDOO\FOLQLFDOO\VLJQLILFDQWFOLQLFDOVDIHW\ODERUDWRU\WHVWYDOXHVYLWDOVLJQVZHLJKW
FKDQJHVDQG(&*SDUDPHWHUYDOXHV

'HYHORSPHQWRIVSHFLILFDQWLHSWLQH]XPDEDQWLERGLHV$'$LQFOXGLQJQHXWUDOL]LQJ
DQWLERGLHV1$EV

&ROXPELD6XLFLGH6HYHULW\5DWLQJ6FDOH&6656VFRUH
6
Analysis Sets
7KHIROORZLQJDQDO\VLVVHWVZLOOEHXVHGWRDQDO\VHDQGSUHVHQWWKHGDWD

DOOSDWLHQWVUDQGRPL]HGVHW$356 DOOUDQGRPL]HGSDWLHQWV

DOOSDWLHQWVWUHDWHGVHW$376 DOOSDWLHQWVLQWKH$356ZKRUHFHLYHGLQIXVLRQZLWK
GRXEOHEOLQG,03

DOOSDWLHQWVWUHDWHGDWLQWHULPVHW$376B,1± DOOSDWLHQWVLQWKH$356ZKRZHUHDPRQJ
WKHILUVWWKDWUHFHLYHGLQIXVLRQZLWKGRXEOHEOLQG,033DWLHQWVZKRUHFHLYHGWKH
LQIXVLRQRQWKHGDWHZKHUHWKHLQIXVLRQQXPEHURFFXUUHGZLOO DOVREHLQFOXGHGLQWKH
FXWRII

DOOSDWLHQWVWUHDWHGLQ'HOD\HG6WDUW3HULRG VHW $376B'6 DOOSDWLHQWVLQWKH$376 ZKR
UHFHLYHGDQLQIXVLRQZLWKGRXEOHEOLQG,03DWWKH:HHN9LVLWDQGDOOSDWLHQWVLQ$376
WKDWZHUHLQWKH3ODFHER&RQWUROOHG3HULRGZKHQUHFUXLWPHQWZDVVWRSSHGDQGKDGD:HHN
9LVLW
7KHHIILFDF\DQDO\VLVIRUWKHLQWHULPDQDO\VLVZLOOEHEDVHGRQWKH$376B,1DQGWKHILQDO
HIILFDF\DQDO\VLVZLOOEHEDVHGRQWKH$356'HPRJUDSKLFVEDVHOLQHFKDUDFWHULVWLFV DQG
VDIHW\WDEOHVZLOO EHEDVHGRQWKH$376 XQOHVVRWKHUZLVHVSHFLILHG
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
7ZRGDWDSRLQWVHWVZLOOEHXVHGIRUSUHVHQWLQJWKHUHVXOWV

'36$OOGDWDSRLQWVREWDLQHGDWRUDIWHUUDQGRPL]DWLRQ

'36$OOGDWDSRLQWVREWDLQHGDWRUDIWHUUDQGRPL]DWLRQEXWSULRUWRSDWLHQWVUHFHLYLQJ
WUDQVLWLRQDOPHGLFDWLRQ*21EORFNDQGRUDOVWHURLGV LQWKH3%2FRQWUROOHG3HULRG 2QO\
SDWLHQWVZLWKDIXOOVWDUWGDWHRIWUDQVLWLRQDOPHGLFDWLRQZLOO EHFDQGLGDWHVIRUH[FOXVLRQ
IURP'36
'36ZLOOEHXVHGIRUDOODQDO\VHVH[FHSWIRUWKHVHQVLWLYLW\DQDO\VLVRIWKHSULPDU\HQGSRLQW
DGGUHVVLQJWKHHIIHFWRIWUDQVLWLRQDOPHGLFDWLRQZKHUH'36ZLOOEHXVHG
$VHSDUDWHLQWHULP6$3ZLOOEHSUHSDUHG
$QLQWHULP&ODVVLILFDWLRQ0HHWLQJZLOOEHKHOGDIWHUWKHGDWDEDVHUHOHDVHIRUWKHSDWLHQWV
IXOILOOLQJWKHFULWHULDIRUSDUWLFLSDWLQJLQWKHLQWHULPDQDO\VLVEXWEHIRUHWKHLUEOLQGLVEURNHQ
$WWKHLQWHULP&ODVVLILFDWLRQ0HHWLQJSDWLHQWVLQWKH$356WKDWZHUHDPRQJWKHILUVW
LQIXVHG,QIXVLRQ,DQGWKRVHZKRUHFHLYHGWKH,QIXVLRQ,RQWKHGDWHZKHUHWKHLQIXVLRQ
QXPEHURFFXUUHGZLOOEHFODVVLILHGLQWRDQDO\VLVVHWV
:KHQDOOLQSDWLHQWV LQ$356 KDYHKDGWKHFKDQFHRIFRPSOHWLQJWKH3ODFHERFRQWUROOHG
3HULRG9LVLW:HHNGDWDFROOHFWHGLQ WKH3ODFHERFRQWUROOHG3HULRGZLOOEHFOHDQHGDQG
ORFNHG
$&ODVVLILFDWLRQ0HHWLQJ ZLOOEHKHOGDIWHUWKHGDWDEDVHUHOHDVHIRUWKHUHSRUWLQJRIWKH
3ODFHERFRQWUROOHG3HULRGEXWEHIRUHWKHEOLQGKDVEHHQEURNHQ3DWLHQWVLQFOXGHGLQWKH
LQWHULPFXWRIIZLOOQRWEHUHFODVVLILHG $Q\GDWDSRLQWVH[FOXGHGIURP'36ZLOOEH
LGHQWLILHGDQGUHFRUGHG $QDO\VHVVSHFLILHGLQWKH6$3IRUGDWDFROOHFWHGLQWKH3ODFHER
FRQWUROOHG3HULRGZLOOWKHQEHSHUIRUPHG
$IWHUDOOSDWLHQWVKDYHFRPSOHWHGWKHVWXG\GDWDZLOOEHFOHDQHGDQGORFNHGWKHGDWDEDVHZLOO
EHUHOHDVHGDQGWKHUHPDLQLQJDQDO\VLVLQWKH6$3ZLOOEHSHUIRUPHG
,QYHVWLJDWRUVDQGSDWLHQWVZLOOEHLQIRUPHGDERXWZKLFKWUHDWPHQWHSWLQH]XPDEPJRU
SODFHERWKH SDWLHQWVUHFHLYHGLQWKH3ODFHERFRQWUROOHG3HULRGRQO\DIWHUWKHODVWSDWLHQWKDV
FRPSOHWHGWKHVWXG\
7
Descriptive Statistics
8QOHVVRWKHUZLVHVSHFLILHGVXPPDU\VWDWLVWLFVQXPEHUVDULWKPHWLFPHDQVWDQGDUGGHYLDWLRQ
>6'@PHGLDQORZHUDQGXSSHUTXDUWLOHVPLQLPXPDQGPD[LPXPYDOXHVZLOOEHSUHVHQWHG
IRUFRQWLQXRXVYDULDEOHVDQGFRXQWVDQGLIUHOHYDQWSHUFHQWDJHVZLOOEHSUHVHQWHGIRU
FDWHJRULFDOYDULDEOHV
8QOHVVRWKHUZLVHVSHFLILHGGDWDOLVWLQJVZLOOLQFOXGHVLWHWUHDWPHQWVSDWLHQWVFUHHQLQJ
QXPEHUVH[DJHUDFHDQGEDVHOLQHZHLJKW
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
8
Patient Disposition
8.1
Summary of Patient Disposition
3DWLHQWGLVSRVLWLRQZLOOEHVXPPDUL]HGE\WUHDWPHQWVDQGE\VLWHDQGWUHDWPHQWVDQGLQFOXGH
WKHQXPEHURISDWLHQWVLQHDFKDQDO\VLVVHWGHILQHGLQFKDSWHU DQGWKHQXPEHURISDWLHQWVLQ
WKH$376ZKRFRPSOHWHGRUZLWKGUHZ7KHVXPPDU\ZLOOEHGRQHIRUWKH3ODFHERFRQWUROOHG
3HULRGDQGIRUWKHVXEVHTXHQW'HOD\HG6WDUW 3HULRG IRU$376B'6
7RDVVHVVWKHSRWHQWLDOLPSDFWRI&29,'RQWKHYLVLWVWUXFWXUHDWDEOHZLOOEHSURYLGHGE\
W\SHRIYLVLWRQVLWHRUUHPRWHDQGWUHDWPHQW VHSDUDWHO\IRUHDFKSHULRGIRUWKHYLVLWVWKDWDUH
FKDQJHGIURPRQVLWHWRUHPRWH7KHVXPPDU\ZLOOEHEDVHGRQ$376
8.2
Withdrawals
7KHQXPEHURISDWLHQWVZKRZLWKGUHZIURPVWXG\GXULQJWKH3ODFHERFRQWUROOHG3HULRGDQG
WKHQXPEHURISDWLHQWVZKRFRPSOHWHGWKH3ODFHERFRQWUROOHG3HULRGZLOOEHVXPPDUL]HGE\
WUHDWPHQWDQGWKHZLWKGUDZDOVIURPVWXG\ZLOODOVREHVXPPDUL]HGE\WUHDWPHQWDQG SULPDU\
UHDVRQIRUZLWKGUDZDODQGE\WUHDWPHQWDQGDOOUHDVRQVIRUZLWKGUDZDO
7KHQXPEHURISDWLHQWVZKRZLWKGUHZIURPWUHDWPHQWZLOOEHVXPPDUL]HGE\WUHDWPHQW DQG
SULPDU\UHDVRQIRUZLWKGUDZDODQGE\WUHDWPHQWDQG DOO UHDVRQV IRUZLWKGUDZDO
7KHQXPEHURISDWLHQWVZKRZLWKGUHZIURPVWXG\GXULQJWKH'HOD\HG6WDUW3HULRGDQGWKH
QXPEHURISDWLHQWVZKRFRPSOHWHGWKH'HOD\HG6WDUW3HULRGZLOOEHVXPPDUL]HGE\WUHDWPHQW
DQGWKHZLWKGUDZDOVIURPVWXG\ZLOODOVREHVXPPDUL]HGE\WUHDWPHQWDQG SULPDU\UHDVRQIRU
ZLWKGUDZDODQGE\WUHDWPHQWDQGDOOUHDVRQVIRUZLWKGUDZDO
3DWLHQWVZKRZLWKGUHZIURPVWXG\DQGSDWLHQWVZKRZLWKGUHZIURPWUHDWPHQW ZLOOEHOLVWHG
DQGWKHOLVWLQJZLOOLQFOXGHWKHQXPEHURIGD\VLQWKHVWXG\XQWLOZLWKGUDZDOWKHQXPEHURI
GD\VVLQFHWKHODVW,03LQIXVLRQWUHDWPHQWSHULRGWKHSULPDU\UHDVRQIRUZLWKGUDZDODOO
UHDVRQVIRUZLWKGUDZDODQGDIODJLIWKHGUXJFRGHZDVEURNHQ
,IQHHGHGDOLVWLQJRISDWLHQWVZKRZLWKGUHZGXHWR&29,'VLWXDWLRQDVWKHSULPDU\
UHDVRQZLOOEHSURYLGHGDVZHOODVDOLVWLQJRISDWLHQWVZLWKGUDZLQJGXHWRIDOOLQJLOORI
&29,'DVWKHSULPDU\UHDVRQ7KHODWWHULVGHILQHGDVSDWLHQWVZLWKGUDZLQJGXHWRDQ
DGYHUVHHYHQWZKLFKLVWKHQVSHFLILHGWREH&29,'
.DSODQ0HLHUIDLOXUHSORWVRIWLPHWRZLWKGUDZDOIURPVWXG\ZLOOEHSUHVHQWHGE\WUHDWPHQW
SHULRGWKDWLVIRUWKH3ODFHERFRQWUROOHG3HULRGDORQHE\WUHDWPHQWDQGIRUWKHSHULRGIURP
%DVHOLQHWRZHHN7KHWLPHZLOOEHFDOFXODWHGIURPWKHGDWHRIILUVWGRVHRI,03LQWKH
WUHDWPHQWSHULRGWRWKHGDWHRIFRPSOHWLRQRUZLWKGUDZDOIURPVWXG\ ZLWKLQWKHVSHFLILHG
WUHDWPHQWSHULRG3DWLHQWVZKRFRPSOHWHGVWXG\ ZLOOEHUHJDUGHGDVFHQVRUHG
$OOWDEOHV DQG JUDSKV ZLOOEHEDVHGRQWKH$376/LVWLQJVZLOOEHEDVHGRQWKH$356
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
9
Demographics and Baseline Characteristics
'HPRJUDSKLFVVH[DJHUDFHUHJLRQFRXQWU\EDVHOLQHFKDUDFWHULVWLFVKHLJKWZHLJKWDQG
%0,DQGEDVHOLQHHIILFDF\YDULDEOHVZLOOEHVXPPDUL]HGIRUWKH3ODFHERFRQWUROOHG3HULRG
E\WUHDWPHQWV $OVRIDPLO\KLVWRU\RIH&+ZLOOEHVXPPDUL]HGE\WUHDWPHQWJURXS
%DVHOLQHGLVHDVHFKDUDFWHULVWLFV7LPHVLQFHVWV\PSWRPV RI&+7LPHVLQFH&+GLDJQRVLV
DQ\SUHYLRXVFKDQJHRYHUWLPHIRUWKH&+SKHQRW\SH FDWHJRULHV1RIURPFKURQLFWR
HSLVRGLFRUIURPHSLVRGLFWRFKURQLFWRHSLVRGLF 7LPHVLQFHVWDUWRIODVWERXW'XUDWLRQRI
ODVWERXW$SSUR[LPDWHQXPEHURIERXWVSHU\HDU$ELOLW\WRSUHGLFWDERXW6HDVRQDOERXW
8VXDOVWDUWWLPH RIDWWDFNV 8VXDOGXUDWLRQRIWKHERXWLQZHHNV8VXDOQXPEHURIDWWDFNV
GD\8VXDOGXUDWLRQRIWKHDWWDFNVLQPLQ8VXDOGXUDWLRQRIWKHUHPLVVLRQSHULRGLQ
PRQWKVDQGWKHDFFRPSDQ\LQJV\PSWRPVZLOOEHVXPPDUL]HGE\WUHDWPHQW
7KHH'LDU\UHSRUWHGEDVHOLQHHIILFDF\YDULDEOHV WKDWZLOOEHVXPPDUL]HGDUHWKHEDVHOLQH
QXPEHURIZHHNO\DWWDFNVEDVHOLQHQXPEHURIWLPHVDERUWLYHPHGLFDWLRQZDVXVHGDQG
EDVHOLQHZHHNO\LQWHJUDWHGPHDVXUHRIIUHTXHQF\DQGLQWHQVLW\RISDLQEDVHOLQHGDLO\PHDQ
SDLQVFRUHZKLFKDUHDOOFROOHFWHGGXULQJWKH6FUHHQLQJ3HULRG
2WKHUEDVHOLQHHIILFDF\YDULDEOHVWKDWZLOOEHVXPPDUL]HGDUH 6,6(4'/ WKHYLVXDO
DQDORJXHVFDOH9$6RIWKHRYHUDOOKHDOWKVWDWH+&58DQG:3$,*+
7UHDWPHQWIDLOXUHPHGLFDWLRQW\SHRIIDLOXUHDQGQXPEHURISUHYLRXVWUHDWPHQWIDLOXUHVZLOO
EHVXPPDUL]HGE\WUHDWPHQW
&RQFXUUHQWDVZHOODVUHOHYDQWSDVWPHGLFDOQHXURORJLFDODQGSV\FKLDWULFGLVRUGHUVZLOOEH
FRGHGXVLQJWKHMedical Dictionary for Regulatory Activities 0HG'5$DQGVXPPDUL]HGE\
WUHDWPHQW6RFLDOKLVWRU\ZLOOEHVXPPDUL]HGE\WUHDWPHQW
$FRQFXUUHQWPHGLFDOQHXURORJLFDO RUSV\FKLDWULFGLVRUGHULVDGLVRUGHUWKDWLVRQJRLQJDWWKH
6FUHHQLQJ9LVLW $SDVWPHGLFDOQHXURORJLFDORUSV\FKLDWULFGLVRUGHULVDGLVRUGHUWKDW
HQGHGSULRUWRWKH6FUHHQLQJ9LVLW 
'HPRJUDSKLFVEDVHOLQHFKDUDFWHULVWLFV DQGEDVHOLQHGLVHDVHFKDUDFWHULVWLFVZLOOEH
VXPPDUL]HGEDVHGRQWKH$376DQGEDVHOLQHHIILFDF\YDULDEOHVZLOOEHVXPPDUL]HGEDVHGRQ
WKH$356
10 Recent and Concomitant Medication
5HFHQWDQGFRQFRPLWDQWPHGLFDWLRQZLOOEHFRGHGXVLQJWKH:+2'UXJ'LFWLRQDU\
:+2''(
)RUWKH3ODFHERFRQWUROOHG3HULRGPHGLFDWLRQVZLOOEHFODVVLILHGDFFRUGLQJWRWKHVWDUWDQG
VWRSWLPHIRUWKHSHULRGDQGVXPPDULVHGE\DQDWRPLFDOWKHUDSHXWLFFKHPLFDO$7&FRGHDQG
JHQHULFGUXJQDPHDQGWUHDWPHQW

PHGLFDWLRQGLVFRQWLQXHGSULRUWR WKHGDWH RI ILUVW,03 LQIXVLRQ
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI

FRQFRPLWDQWPHGLFDWLRQWDNHQ LQWKH3ODFHERFRQWUROOHG3HULRG
0HGLFDWLRQVZLWKDVWDUWGDWHDW RUDIWHUWKHGDWHRIILUVW,03LQIXVLRQDQGSULRUWRWKH
GDWHRIVHFRQG ,03LQIXVLRQ PHGLFDWLRQVZLWKDVWRSGDWHDWRUDIWHUWKHGDWHRIILUVW
,03LQIXVLRQWKDWDOVRKDYHDVWDUW GDWHSULRUWRWKHGDWHRIVHFRQG ,03LQIXVLRQDQG
PHGLFDWLRQVZKHUHERWKVWDUWDQGVWRS GDWHDUHFRPSOHWHO\PLVVLQJ2QJRLQJ
PHGLFDWLRQVZLWKDVWDUWGDWHSULRUWRWKHGDWHRIVHFRQG ,03LQIXVLRQDUHDOVR
LQFOXGHGDVZHOODVPHGLFDWLRQVZLWKDVWDUWGDWHSULRUWRWKHGDWH RIVHFRQG ,03
LQIXVLRQZLWKDFRPSOHWHO\PLVVLQJVWRSGDWH)RUSDWLHQWVWKDWZHUHLQWKH3ODFHER
&RQWUROOHG3HULRGZKHQUHFUXLWPHQWZDVVWRSSHGWKHVWDUWGD\VKRXOGEHSULRUWRWKH
:HHN9LVLWGDWHLQVWHDGRISULRUWRWKHVHFRQG,03LQIXVLRQ
)RUWKH'HOD\HG6WDUW 3HULRGFRPELQHGPHGLFDWLRQVZLOOEHFODVVLILHGDFFRUGLQJWRWKHVWDUW
DQGVWRSWLPHIRUWKHSHULRGDQGVXPPDULVHGE\DQDWRPLFDOWKHUDSHXWLFFKHPLFDO$7&FRGH
DQGJHQHULFGUXJQDPHDQGWUHDWPHQW

FRQFRPLWDQWPHGLFDWLRQFRQWLQXHGDIWHUWKHGDWH RI VHFRQG ,03LQIXVLRQRUDIWHUWKHGDWH
RIWKH:HHN9LVLWIRUSDWLHQWVWKDWZHUHLQWKH3ODFHERFRQWUROOHG3HULRGZKHQ
UHFUXLWPHQWZDVVWRSSHG

FRQFRPLWDQWPHGLFDWLRQVWDUWHGDWRUDIWHUWKHGDWH RI VHFRQG,03 LQIXVLRQ DQGEHIRUHWKH
VWXG\HQGGDWHRUDW RUDIWHUWKHGDWHRIWKH:HHN9LVLWDQGEHIRUHWKHVWXG\HQGGDWHIRU
SDWLHQWVWKDWZHUHLQWKH3ODFHERFRQWUROOHG3HULRGZKHQUHFUXLWPHQWZDVVWRSSHG
$OOGLVDOORZHGPHGLFDWLRQVZLOOEHOLVWHGEDVHGRQWKH$3567KHOLVWLQJZLOOLQFOXGHWKH
JHQHULFGUXJQDPHWKHGXUDWLRQWKHVWDUWDQGHQGGDWHVDQGGRVLQJLQIRUPDWLRQ
)RUWKHUHSRUWLQJRISUHYHQWLYHDQGDERUWLYHPHGLFDWLRQIRUWUHDWPHQWRI&+WKHIROORZLQJ
ZLOOEHUHSRUWHG

1XPEHURISDWLHQWVWDNLQJDERUWLYHPHGLFDWLRQZLOOEHVXPPDUL]HGIRUEDVHOLQHSHULRG
3ODFHERFRQWUROOHGSHULRGDQG'HOD\HG6WDUW 3HULRG

1XPEHURISDWLHQWVXVLQJSUHYHQWLYHPHGLFDWLRQVZLOOEHVXPPDUL]HGIRUWKHEDVHOLQH
SHULRGDQGWKH3ODFHERFRQWUROOHGSHULRGDQGWKHWRWDOQXPEHURISDWLHQWVXVLQJSUHYHQWLYH
PHGLFDWLRQVZLOODOVREHVXPPDUL]HG
3UHYLRXVXVHRIPHGLFDWLRQ PHGLFDWLRQIRUWUHDWPHQWRI&+ ZLOOEHVXPPDUL]HG E\WUHDWPHQW
1XPEHURISDWLHQWVXVLQJWUDQVLWLRQDOPHGLFDWLRQV *21EORFNDQGRUDOVWHURLGVZLOOEH
VXPPDUL]HGIRUWKH'HOD\HG6WDUWSHULRG ,IWUDQVLWLRQDOPHGLFDWLRQV *21EORFNDQGRUDO
VWHURLGVDUHXVHG LQWKH 3ODFHERFRQWUROOHG3HULRG WKHFDVHVZLOOEHOLVWHG
11 Exposure
)RUHDFKSHULRGWKHQXPEHURILQIXVLRQVUHFHLYHGWKHQXPEHUFRPSOHWHGDVSODQQHGWKH
QXPEHULQWHUUXSWHG DQGUHVWDUWHGDQGWKHQXPEHUWKDWODVWHGORQJHUOHVV WKDQ
PLQXWHVZLOOEHVXPPDUL]HGE\WUHDWPHQW
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
3DWLHQWVZKRDWDQ\SRLQWGXULQJWKHVWXG\UHFHLYHGDGLIIHUHQWWUHDWPHQWWKDQZKDWZDV
SODQQHGZLOOEHOLVWHG7KHOLVWLQJZLOOLQFOXGHDOOLQIXVLRQYLVLWVGDWHVRILQIXVLRQYLVLWV
SODQQHGWUHDWPHQWIRUWKHSDWLHQWDQGDFWXDOWUHDWPHQWUHFHLYHGIRUWKHSDWLHQW
,QDGGLWLRQDOOLQIXVLRQGDWDZLOOEHOLVWHGLHWKHVWDUWDQGVWRSWLPHRIWKHLQIXVLRQDQGWKH
GXUDWLRQRIWKHLQIXVLRQ
12 eDiary Compliance
7KHSURSRUWLRQ RIGD\VZLWKQRQFRPSOLDQFHZLWKWKHH'LDU\ZLOOEHVXPPDUL]HGDQG
SUHVHQWHGE\ZHHNLQWHUYDO DQG WUHDWPHQW IRUHDFKSHULRG)XUWKHUPRUHWKHQXPEHURI
SDWLHQWVPLVVLQJGD\VRUPRUHLQDGD\SHULRGZLOOEHSUHVHQWHGE\ZHHNLQWHUYDO DQG
WUHDWPHQWIRUHDFKSHULRG
$GD\RIQRQFRPSOLDQFHLVGHILQHGDVDGD\ZKHUHWKHVXEMHFWGLGQRWUHSRUW DQ\ DWWDFNV LQ
WKHH&+ H'LDU\DQGDOVRGLGQRWFRQILUPQRDWWDFNVLQWKHHYHQLQJ H'LDU\
7KHVXPPDULHVZLOOEHEDVHGRQWKH$356
13 Efficacy
13.1 General Efficacy Analysis Methodology
8QOHVVRWKHUZLVHVSHFLILHGDOOHIILFDF\DQDO\VHVZLOOEHEDVHGRQWKH $356
$OOWDEOHVDQGJUDSKVZLOOEHSUHVHQWHGE\WUHDWPHQW
$OOSYDOXHVZLOOEHEDVHGRQWZRVLGHGWHVWV WKHHQGSRLQWVZLOOEHSUHVHQWHGZLWKWZRVLGHG
FRQILGHQFHLQWHUYDOV&,V7KHHQGSRLQWVQRWLQFOXGHGLQWKHWHVWLQJVWUDWHJ\ZLOOEH
SUHVHQWHGZLWKSYDOXHVDQG&,V
$SDUWIURP WKHH[SORUDWRU\HQGSRLQWµ7LPHIURPLQIXVLRQWRUHVROXWLRQRIFOXVWHU KHDGDFKH
ERXWZLWKLQZHHNV¶ ZKLFKZLOORQO\EHSUHVHQWHGIRUSDWLHQWVUDQGRPLVHGWRHSWLQH]XPDE
GXULQJWKHSODFHERFRQWUROOHGSKDVH WKH HIILFDF\GDWDIURPWKH'HOD\HGVWDUWSHULRG
H[FOXGLQJWKHVDIHW\IROORZXSSHULRGZLOORQO\EHSUHVHQWHGGHVFULSWLYHO\
13.2 Testing Strategy
3ULPDU\HQGSRLQW

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV:HHNV
.H\VHFRQGDU\HQGSRLQWV LQKLHUDUFKLFDORUGHU

5HVSRQVHUHGXFWLRQIURP%DVHOLQHLQ WKH QXPEHURIZHHNO\DWWDFNV:HHNV
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\WLPHVDQDERUWLYHPHGLFDWLRQZDVXVHG
:HHNV 

&KDQJHIURP%DVHOLQHLQWKHQXPEHURIGDLO\DWWDFNV'D\V

&KDQJHIURP%DVHOLQHLQWKH QXPEHURIZHHNO\GD\VZLWK DWWDFNVSHUGD\:HHNV

7LPHIURPILUVWLQIXVLRQRI,03WRUHVROXWLRQRIFOXVWHUKHDGDFKHERXWZLWKLQWKHILUVW
ZHHNV

1XPEHURIDWWDFNVVWDUWLQJ KRXUVDIWHU WKHVWDUWRIWKHILUVWLQIXVLRQ RI,03
$ WZRVLGHGVLJQLILFDQFHOHYHORI ZLOOEHXVHGIRUWKHIRUPDOKLHUDUFKLFDOWHVWLQJVWUDWHJ\
7KHWHVWLQJVWUDWHJ\ZLOOEHDVHTXHQFHRIWHVWVWHVWLQJRQHHQGSRLQWDWDWLPH2QO\LIRQH
VWHSKDVVKRZQDVWDWLVWLFDOO\VLJQLILFDQWHIIHFWZLOOWKHIRUPDOWHVWLQJFRQWLQXHZLWKWKHQH[W
VWHSWKXVHQVXULQJSURWHFWLRQRIWKHW\SHHUURU7KHVWHSVDUHGHVFULEHGEHORZ
Step 1
7HVWWKHSULPDU\HQGSRLQWXVLQJDVLJQLILFDQFHOHYHO,IWKHSULPDU\HQGSRLQWVKRZVDQ
DGYDQWDJHRXVHIIHFWRIHSWLQH]XPDEFRPSDUHG WRSODFHERWKHHIIHFWVHHQIRUWKHSULPDU\
HQGSRLQWLVFRQVLGHUHGVWDWLVWLFDOO\VLJQLILFDQWDQGWKHWHVWLQJFRQWLQXHVZLWKWKHQH[WVWHS
Step 2
7HVWWKHILUVWNH\VHFRQGDU\HQGSRLQWXVLQJDVLJQLILFDQFHOHYHO,IWKHILUVWNH\
VHFRQGDU\HQGSRLQWVKRZVDQDGYDQWDJHRXVHIIHFWRIHSWLQH]XPDEFRPSDUHGWRSODFHERWKH
HIIHFWVHHQIRUWKHILUVWNH\VHFRQGDU\HQGSRLQWLVFRQVLGHUHGVWDWLVWLFDOO\VLJQLILFDQWDQGWKH
WHVWLQJFRQWLQXHVZLWKWKHQH[WVWHSIRUWKHVHFRQGNH\VHFRQGDU\HQGSRLQW
Step 3
7KHVWHSVIRUWHVWLQJWKHNH\VHFRQGDU\HQGSRLQWVLQWKHRUGHUVWDWHGLQWKHEHJLQQLQJRIWKLV
VHFWLRQFRQWLQXHVXQWLODSYDOXH!  LVHQFRXQWHUHGRUDOONH\VHFRQGDU\HQGSRLQWVDUH
IRXQGWREHVWDWLVWLFDOO\VLJQLILFDQW
13.3 Analysis Methodology for the Primary Endpoint
13.3.1
Primary Estimand
7KHSULPDU\HVWLPDQGZLOOEHWKHPHDQGLIIHUHQFHLQFKDQJHIURP%DVHOLQHLQWKHQXPEHURI
ZHHNO\DWWDFNV:HHNVEHWZHHQSDWLHQWVZLWKHSLVRGLFFOXVWHUKHDGDFKHWUHDWHGZLWK
HSWLQH]XPDEDQGSODFHERZLWKRXWXVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDO
VWHURLGVDQGUHJDUGOHVVRIXVHRIDERUWLYH RU SUHYHQWLYHPHGLFDWLRQDQGLQIXVLRQLQWHUUXSWLRQ
RUWHUPLQDWLRQEHIRUHIXOOGRVHLVUHFHLYHG
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Intercurrent Events 
7KHIROORZLQJLQWHUFXUUHQWHYHQWVRFFXUULQJDIWHUWUHDWPHQWLQLWLDWLRQDQGSRWHQWLDOO\DIIHFWLQJ
HLWKHUWKHLQWHUSUHWDWLRQRUWKHH[LVWHQFHRIWKHPHDVXUHPHQWVDVVRFLDWHGZLWKWKHFOLQLFDO
TXHVWLRQRILQWHUHVWDUHFRQVLGHUHG

7UDQVLWLRQDOPHGLFDWLRQ IRUFOXVWHUKHDGDFKH *21EORFNDQGRUDOVWHURLGV

,QWHUUXSWLRQRI,03 ,QIXVLRQVWRSSHG SUHPDWXUHO\
Attributes of the primary estimand
7KHSULPDU\HVWLPDQGKDVWKHIROORZLQJDWWULEXWHV

7KHtreatment condition of interest ZLOOEHWKHFRPSDULVRQRIHSWLQH]XPDEWRSODFHER
ZLWKRXWWKHXVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVDQGZLWKRU
ZLWKRXWWKHXVHRIDERUWLYH RUSUHYHQWLYHPHGLFDWLRQIRUFOXVWHUKHDGDFKH

7KHpopulation of interest ZLOOEHDOOSDWLHQWVZLWKHSLVRGLFFOXVWHUKHDGDFKHWKDWIXOILOWKH
LQFOXVLRQDQGQRQHRIWKHH[FOXVLRQFULWHULD

7KHendpoint to be obtained to address the clinical question LVFKDQJHIURP%DVHOLQHLQ
WKHQXPEHURIZHHNO\DWWDFNV :HHNV

7KHintercurrent events: XVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVRU
LQWHUUXSWLRQRUSUHPDWXUHO\VWRSSLQJ,03LQIXVLRQZLOOEHDGGUHVVHGE\WUHDWPHQWSROLF\
VWUDWHJLHV

7KHpopulation level summary ZLOOEHWKHPHDQGLIIHUHQFHLQWKHSULPDU\HQGSRLQW
EHWZHHQHSWLQH]XPDEDQGSODFHER
13.3.2
Rationale for the Primary Estimand
7KHQXPEHURIZHHNO\DWWDFNVLVFRQVLGHUHGDJRRGPHDVXUHRIWKHGLVHDVHEXUGHQLQHSLVRGLF
FOXVWHUKHDGDFKHDQGWKHUHIRUHZLOOEHXVHGIRUWKHSULPDU\HQGSRLQW
Justification of Treatment Condition of Interest
7KHXVHRIDERUWLYHPHGLFDWLRQWULSWDQVDQG2LVLQFOXGHGLQWKHWUHDWPHQWFRQGLWLRQRI
LQWHUHVWEHFDXVHDERUWLYHPHGLFDWLRQLVWDNHQ DIWHUDQDWWDFNEHJLQVWRDIIHFWWKDWVSHFLILF
DWWDFN,WLVQRWH[SHFWHG WKDWWKHXVHRIDERUWLYHPHGLFDWLRQZLOO DIIHFW WKHQXPEHURI DWWDFNV
IROORZLQJDQDWWDFNZKHUHDERUWLYHPHGLFDWLRQZDVWDNHQ7KXVWKHXVHRIDERUWLYH
PHGLFDWLRQLVQRWFRQVLGHUHGWREHDQLQWHUFXUUHQWHYHQW
7KHXVHRISUHYHQWLYHPHGLFDWLRQLVLQFOXGHGLQWKHWUHDWPHQWFRQGLWLRQRILQWHUHVWEHFDXVH
HSWLQH]XPDELVH[SHFWHGWREHXVHGZLWKRUZLWKRXWRWKHUSUHYHQWLYHPHGLFDWLRQ IRUSDWLHQWV
VXIIHULQJIURPHSLVRGLF FOXVWHUKHDGDFKH)XUWKHUPRUHWKRXJKWKHXVHRISUHYHQWLYH
PHGLFDWLRQFRXOGLQIOXHQFHWKHQXPEHURIDWWDFNVWKHSRWHQWLDOHIIHFWLVH[SHFWHGWREHOLPLWHG
LQDQ HSLVRGLF FOXVWHUKHDGDFKHSRSXODWLRQ7KXVWKHXVHRISUHYHQWLYHPHGLFDWLRQLV QRW
FRQVLGHUHGWREHDQLQWHUFXUUHQWHYHQW
Intercurrent events:
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI

8VHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVIRUFOXVWHUKHDGDFKH±
DGGUHVVHGE\DWUHDWPHQWSROLF\VWUDWHJ\
7KHWUHDWPHQWHIIHFWRILQWHUHVWLVLQSDWLHQWVZLWKRXWXVHRIWUDQVLWLRQDOPHGLFDWLRQV
VLQFHWKHWUHDWPHQWLVPDLQO\FRQVLGHUHGDVDQDOWHUQDWLYHUDWKHUWKDQDQDGGRQWR
WUDQVLWLRQDOPHGLFDWLRQ8VHRIWUDQVLWLRQDOPHGLFDWLRQ LVGLVDOORZHGIURPGD\V
SULRUWRILUVW,03DQGIRUWKHILUVWZHHNVDIWHUILUVW,03DFFRUGLQJWRWKHSURWRFRO
PHDQLQJWKDWWKHFROOHFWHGGDWDLQWKLVZD\ZLOOHVWLPDWHWKHHIIHFWLQSDWLHQWVZLWKRXW
XVHRIWUDQVLWLRQDOPHGLFDWLRQV GXULQJWKH3ODFHERFRQWUROOHG3HULRG6KRXOG
WUDQVLWLRQDOPHGLFDWLRQ EHXVHGGXULQJWKHILUVWZHHNVDIWHUILUVW,03GHVSLWHLW
EHLQJGLVDOORZHGLWZLOOEHDGGUHVVHGXVLQJDWUHDWPHQWSROLF\VWUDWHJ\

,QWHUUXSWLRQRUSUHPDWXUHO\VWRSSLQJ,03LQIXVLRQ± DGGUHVVHGE\DWUHDWPHQWSROLF\
VWUDWHJ\
7KHSULPDU\HVWLPDQGWDUJHWVWKHHIIHFWVHHQUHJDUGOHVVRI LQWHUUXSWLRQRU
SUHPDWXUHO\VWRSSLQJ,03LQIXVLRQ7KLVLVFRQVLGHUHGDFRQVHUYDWLYHDSSURDFKDV
VXFKGLVWXUEDQFHVDUHPDLQO\H[SHFWHGWRDIIHFWWKHDFWLYHWUHDWPHQW
13.3.3
Primary Analysis 
7KHFOLQLFDOTXHVWLRQRILQWHUHVWLVZKHWKHUWKHQXPEHURIDWWDFNVLVUHGXFHGPRUHZLWK
HSWLQH]XPDEWKDQZLWKSODFHERGXULQJWKHILUVWZHHNVDIWHULQIXVLRQ
7KHSULPDU\HQGSRLQWWKDWZLOODGGUHVVWKHFOLQLFDOTXHVWLRQRILQWHUHVWZLOOEHWKHFKDQJH
IURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV:HHNV7KHHQGSRLQWLVEDVHGRQH'LDU\
GDWDRQDWWDFNVDQGWKHDYHUDJHQXPEHURIZHHNO\DWWDFNV DFURVV:HHNDQG:HHNZLOOEH
HVWLPDWHGDVSUHVHQWHGEHORZ
7KHVWUDWHJ\ IRULPSXWDWLRQRIPLVVLQJGDWD LVJLYHQEHORZDQGLQGHWDLOVLQ FKDSWHU 

)RUHDFKZHHNO\VFRUHLQFOXGLQJWKH%DVHOLQH3HULRGSURUDWLQJLVXVHG WRLPSXWHDQ\
PLVVLQJGDWDZKHUHWKHH'LDU\LVFRPSOHWHGRQDWOHDVWRXWRIWKHGD\VWRKDYHIXOO
ZHHNO\VFRUHV

)RUSDWLHQWVZLWKGD\VZLWKREVHUYDWLRQVGXULQJWKH%DVHOLQH3HULRGWKHPLVVLQJ
EDVHOLQHQXPEHURIZHHNO\DWWDFNVZLOOEHGUDZQIURPDQRUPDOGLVWULEXWLRQZLWKWKH
PHDQDQG6'WDNHQIURPWKHEDVHOLQHQXPEHURIZHHNO\DWWDFNVIRUSDWLHQWVZKHUHD
EDVHOLQHQXPEHURIZHHNO\DWWDFNVKDVEHHQREWDLQHGIURPSDWLHQWVZLWKDWOHDVWRI
GD\VRIREVHUYDWLRQVDQGSRVVLEO\XVLQJSURUDWLQJIRUWKHFDOFXODWLRQ,IQHHGHGWKLVVWHS
ZLOOEHLQFRUSRUDWHGDVWKHLQLWLDOVWHSRIWKH SODFHEREDVHGPXOWLSOHLPSXWDWLRQ S0,
DQDO\VLVDQGWKXVQHZUDQGRPEDVHOLQHYDOXHVZLOOEHGUDZQIRUHDFKRIWKH
VLPXODWHGGDWDVHWVLQFDVHRIPLVVLQJEDVHOLQHYDOXHVVHH$SSHQGL[,,
7KHSULPDU\DQDO\VLVZLOOXVHDS0,PHWKRG6SHFLILFDOO\DQDQDO\VLVZLOOEHSHUIRUPHG
XVLQJDSDWWHUQPL[WXUHPRGHO300LQZKLFKDIWHUDSSOLFDWLRQRIWKHSURUDWLQJUXOH WRGDWD
DQ\PLVVLQJZHHNO\VFRUHV ZLOOEHLPSXWHGXVLQJDVHTXHQWLDOUHJUHVVLRQEDVHGPXOWLSOH
LPSXWDWLRQPHWKRGEDVHGRQWKHLPSXWDWLRQPRGHOVHVWDEOLVKHGIURPWKHSODFHERJURXS
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
7KHS0,ZLOOJHQHUDWHVLPXODWHGGDWDVHWV ZLWKFRPSOHWHDVVHVVPHQWRIQXPEHURIZHHNO\
DWWDFNVIRU:HHNVDQG )RUGHWDLOVRQSRWHQWLDOPLVVLQJEDVHOLQHVFRUHV SOHDVHVHH
VHFWLRQ 
7KHVWHSVRIWKHPXOWLSOHLPSXWDWLRQDQDO\VLVXVLQJWUDMHFWRU\RIWKHSODFHERWUHDWPHQWZLOOEH
WKHIROORZLQJ

8VH6$6352&0,XVLQJ0&0&WRJHQHUDWHGDWDVHWVDQGHQVXUHWKDWDOOSDWLHQWV
RQO\KDYHPRQRWRQHPLVVLQJGDWDXVLQJDVHHGRI

8VH6$6352&0,ZLWKPRQRWRQHUHJUHVVLRQWRFRPSOHWHWKHGDWDVHWVZKHUHWKH
PLVVLQJGDWDIRUZHHNO\VFRUHVDUHLPSXWHG01$5DFFRUGLQJWRWKHSODFHERWUHDWPHQW
ERWKIRUSDWLHQWVUDQGRPLVHGWRHSWLQH]XPDEDQGSODFHERXVLQJDVHHGRI

$QDO\VHHDFKRIWKHGDWDVHWVDFFRUGLQJWRWKH0050PRGHOGHVFULEHGEHORZ

8VH6$6352&0,$1$/<=(WRFRPELQHWKHUHVXOWVIURPWKHDQDO\VHVDFFRUGLQJWR
5XELQ¶V5XOH
6$6FRGHWKDWLOOXVWUDWHVWKHNH\VWHSVRIWKHS0,DQDO\VLVDERYHLVVKRZQLQ $SSHQGL[,,
)URPWKHS0, DQDO\VLVWKHHVWLPDWHVWDQGDUGHUURUFRQILGHQFHLQWHUYDOWWHVWVWDWLVWLF
DQGSYDOXHZLOOEHSUHVHQWHG
MMRM model
7KH0050PRGHO ZLOODQDO\VHWKHFKDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV
XVLQJDUHVWULFWHGPD[LPXPOLNHOLKRRG5(0/EDVHGPL[HGPRGHOIRUUHSHDWHGPHDVXUHV
0050 DSSURDFK
7KH0050PRGHOEDVHGRQGDWDIURPDOOZHHNVLQWKH3%2FRQWUROOHGSHULRGZLOOLQFOXGH
WKHIROORZLQJIL[HGHIIHFWVZHHN  FRXQWU\DQGWUHDWPHQWDVIDFWRUVEDVHOLQHVFRUH
DVDFRQWLQXRXVFRYDULDWH WUHDWPHQWE\ZHHN LQWHUDFWLRQDQGEDVHOLQHVFRUHE\ZHHN
LQWHUDFWLRQ$QXQVWUXFWXUHGYDULDQFHVWUXFWXUHZLOOEHXVHGWRPRGHOWKHZLWKLQSDWLHQWHUURUV
7KH.HQZDUG5RJHU DSSUR[LPDWLRQZLOOEHXVHGWRHVWLPDWHGHQRPLQDWRUGHJUHHVRIIUHHGRP
7KHPHDQGLIIHUHQFHEHWZHHQHSWLQH]XPDEDQGSODFHERLQWKH&KDQJHIURP%DVHOLQHLQWKH
QXPEHURIZHHNO\DWWDFNV:HHNVZLOOEHHVWLPDWHGEDVHGRQOHDVWVTXDUHPHDQVIRUWKH
WUHDWPHQWE\ZHHNLQWHUDFWLRQXVLQJZHLJKWVIRUWKHHSWLQH]XPDEE\ZHHN
HVWLPDWHVDQGZHLJKWVIRUWKHSODFHERE\ZHHNHVWLPDWHV 7KH6$6FRGHIRU
WKH0050PRGHOLVVKRZQLQ $SSHQGL[,,
7RLQYHVWLJDWHWKHLPSDFWRIWKHPLVVLQJQRWDWUDQGRP01$5 DVVXPSWLRQ XVHGIRUWKH
SULPDU\DQDO\VLVDQDGGLWLRQDOVHQVLWLYLW\DQDO\VLVZLOOEHSHUIRUPHG LQZKLFKDVLPLODU
PXOWLSOHLPSXWDWLRQDQDO\VLVZLOOEHFRQGXFWHGDVIRUWKHSULPDU\HQGSRLQWEXWZKHUHPLVVLQJ
GDWDZLOOEHLPSXWHGDFFRUGLQJWRWKHUDQGRPLVHGWUHDWPHQWZLWKHSWLQH]XPDERUSODFHER7KH
PHDQGLIIHUHQFHEHWZHHQHSWLQH]XPDEDQGSODFHERLQWKH&KDQJHIURP%DVHOLQHLQWKH
 7KHVHHGZDVXVHGIRUWKHLQWHULPDQDO\VLV
 7KHVHHGZDVXVHGIRUWKHLQWHULPDQDO\VLV
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
QXPEHURIZHHNO\DWWDFNV:HHNVZLOOEHHVWLPDWHGEDVHGRQOHDVWVTXDUHPHDQVIRUWKH
WUHDWPHQWE\ZHHNLQWHUDFWLRQXVLQJZHLJKWVIRUWKHHSWLQH]XPDE E\ZHHN
HVWLPDWHVDQGZHLJKWVIRUWKHSODFHERE\ZHHNHVWLPDWHV
7KHSULPDU\DQDO\VLVZLOOEHEDVHGRQWKH$356XVLQJWKH'36'DWDSRLQWVHWZLWKDOO
REVHUYDWLRQVLQFOXGHG
13.3.4
Rationale for Selected Analysis Method for the Primary Endpoint
7KHGDWDIURPWKHH'LDU\ZLOOEHLPSXWHGDFFRUGLQJWRWKHUXOHDERYHXVLQJSURUDWLQJVHH
VHFWLRQ DQGWKHQDQDO\VHGXVLQJWKHDERYHGHVFULEHGS0, PRGHO
7KH0050PRGHOLVFKRVHQDVLWLVDYHU\IOH[LEOHDQGUREXVWDQDO\VLVDQGZLWKWKHVHOHFWHG
H[SODQDWRU\YDULDEOHVLWZLOODOORZWUHDWPHQWWRYDU\IUHHO\E\ZHHNDFFRXQWIRUWKHEDVHOLQH
OHYHODQGIRUWKHVWUDWLILFDWLRQE\FRXQWU\DQGLQFOXGHWKHPRVW IOH[LEOHVWUXFWXUHIRUZLWKLQ
SDWLHQWYDULDWLRQ
7KHPXOWLSOHLPSXWDWLRQDQDO\VLV ZLOOHQVXUHWKDWDOOUDQGRPLVHGSDWLHQWVDUHLQFOXGHGLQWKH
SULPDU\DQDO\VLVDQGWKHVWUDWHJ\FKRVHQZLOOLPSXWHPLVVLQJGDWDIRUSDWLHQWVWUHDWHGZLWK
HSWLQH]XPDEDVLIWKH\ZHUHWUHDWHGZLWKSODFHERWRHQVXUHWKDWWKHUHVXOWRIWKHSULPDU\
DQDO\VLVOLNHO\ZLOOEHFRQVHUYDWLYH
13.3.5
Sensitivity Analyses of the Primary Endpoint
13.3.5.1 Sensitivity Analyses to assess the impact of missing observations
7RDVVHVVWKHLPSDFWRILPSXWLQJPLVVLQJREVHUYDWLRQVRQHSWLQH]XPDEEDVHGRQWKHSODFHER
WUHDWPHQWWKH0050PRGHOGHVFULEHGDERYHZLOOEHXVHGWRDQDO\VHWKHGDWDZKHUH
SURUDWLQJKDVEHHQXVHGIRUZHHNO\VFRUHVZLWKDWOHDVWGD\VZLWKREVHUYDWLRQVEXWZKHUHQR
IXUWKHULPSXWDWLRQVKDYHEHHQSHUIRUPHG
7KHPHDQGLIIHUHQFHEHWZHHQHSWLQH]XPDEDQGSODFHERZLOOEHHVWLPDWHGEDVHGRQWKHOHDVW
VTXDUHVPHDQVIRUWKHWUHDWPHQWE\ZHHNLQWHUDFWLRQLQWKH0050PRGHO 7KHPHDQ
GLIIHUHQFHEHWZHHQHSWLQH]XPDEDQGSODFHERLQWKH&KDQJHIURP%DVHOLQHLQWKHQXPEHURI
ZHHNO\DWWDFNV:HHNVZLOOEHHVWLPDWHGEDVHGRQOHDVWVTXDUHPHDQVIRUWKHWUHDWPHQW
E\ZHHNLQWHUDFWLRQXVLQJZHLJKWVIRUWKHHSWLQH]XPDEE\ZHHNHVWLPDWHVDQG
ZHLJKWVIRUWKHSODFHERE\ZHHNHVWLPDWHV 7KHHVWLPDWHVZLOOEHSUHVHQWHG
ZLWKSYDOXHVDQG&,V
13.3.5.2 Sensitivity analysis to assess the impact of use of transitional medication for 
eCH
7UDQVLWLRQDOPHGLFDWLRQV *21EORFNDQGRUDOVWHURLGVZKLFKDUH RIWHQXVHGGXULQJDWLPH
ZKHUHWKHHIIHFWRIWKHFXUUHQWO\DYDLODEOHSUHYHQWLYHPHGLFDWLRQKDVQRW\HWVHWLQDQGFDQ
KHQFHEHFRQVLGHUHGDVDW\SHRIUHVFXHPHGLFDWLRQFRXOGSRWHQWLDOO\HQGWKHERXWRIFOXVWHU
KHDGDFKHVDQGKHQFHWKHWUHDWPHQWHIIHFWLVFRQVLGHUHGUHOHYDQWLILWLV VHHQLQSDWLHQWVZLWKRXW
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
WKHXVHRIWUDQVLWLRQDOPHGLFDWLRQV7KXVDVHQVLWLYLW\DQDO\VLVLVDGGHGWRPRUHSUHFLVHO\
DVVHVVWKHHIIHFWXQGHUVXFKFLUFXPVWDQFHVE\FRQVLGHULQJWKHLPSDFWRILQFOXGLQJGDWDDIWHU
WKHXVHRIWUDQVLWLRQDOPHGLFDWLRQ
7KHLPSDFWRIXVHRIWUDQVLWLRQDOPHGLFDWLRQ*21EORFN DQG RUDOVWHURLGVIRUFOXVWHU
KHDGDFKHVZLOOEHDGGUHVVHGXQGHUDK\SRWKHWLFDOVWUDWHJ\RIQRWUDQVLWLRQDOPHGLFDWLRQ EHLQJ
DYDLODEOH8QGHUWKHVHK\SRWKHWLFDOFLUFXPVWDQFHVLWLVDVVXPHGWKDWWKHHIIHFWZRXOGEH
VLPLODUWRRWKHUSDWLHQWVZLWKVLPLODUSUHYLRXVVFRUHVLQWKHSODFHER WUHDWPHQWDQGWKHDQDO\VLV
ZLOOEHFRQGXFWHGE\UHPRYLQJDQ\H'LDU\GDWDLQWKH3%2FRQWUROOHG3HULRGDIWHUWKHXVHRI
WUDQVLWLRQDOPHGLFDWLRQ DVWKXVXVH$356EXWIRUWKH'36GDWDSRLQWVHWRQO\LQFOXGLQJGDWD
SRLQWVREWDLQHGDWRUDIWHUUDQGRPL]DWLRQEXWSULRUWRSDWLHQWVUHFHLYLQJWUDQVLWLRQDO
PHGLFDWLRQ*21EORFNDQGRUDOVWHURLGV %DVHGRQWKLVGDWDWKHSURUDWLQJZLOOEHUHGRQH WR
JHQHUDWHDQHZGDWDVHW VHHGHWDLOVLQVHFWLRQ  7KHQHZGDWDVHWZLOOEHDQDO\VHG
XVLQJWKH0050PRGHOGHVFULEHGLQ WKHSULPDU\DQDO\VLVVHFWLRQ
13.4 Analysis Methodology for the Key Secondary Endpoints
13.4.1
Analysis of the Key Secondary Endpoints
7KHWHVWLQJVWUDWHJ\IRUWKHNH\VHFRQGDU\HQGSRLQWVLVGHVFULEHGLQVHFWLRQ 
13.4.1.1 Continuous endpoints 
7KHHVWLPDQGVIRUWKHFRQWLQXRXVHQGSRLQWV&KDQJHIURP%DVHOLQHLQWKHQXPEHURIGDLO\
DWWDFNV'D\V&KDQJHIURP%DVHOLQHLQWKH QXPEHURIZHHNO\GD\VZLWK DWWDFNVSHU
GD\:HHNVDQG1XPEHURIDWWDFNVVWDUWLQJ KRXUVDIWHUWKHVWDUWRIWKHILUVW
LQIXVLRQ RI,03 VKDUHDWWULEXWHV

7KHtreatment condition of interest ZLOOEHWKHFRPSDULVRQRIHSWLQH]XPDE PJWR
SODFHERZLWKRXWWKHXVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVDQGZLWK
RUZLWKRXWWKHXVHRIDERUWLYH RU SUHYHQWLYHPHGLFDWLRQIRUFOXVWHUKHDGDFKH

7KHpopulation of interest ZLOOEHDOOSDWLHQWVZLWKHSLVRGLFFOXVWHUKHDGDFKHWKDWIXOILOWKH
LQFOXVLRQDQGH[FOXVLRQFULWHULD

7KHintercurrent events: XVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVRU
LQWHUUXSWLRQRUSUHPDWXUHO\VWRSSLQJ,03LQIXVLRQZLOOEHDGGUHVVHGE\DWUHDWPHQWSROLF\
VWUDWHJ\

7KHpopulation level summary ZLOOEHWKHPHDQGLIIHUHQFHLQWKHHQGSRLQWEHWZHHQ
HSWLQH]XPDE PJDQGSODFHER
,QDGGLWLRQWKHHQGSRLQW&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\WLPHVDQDERUWLYH
PHGLFDWLRQZDVXVHG:HHNV  VKDUHVWKHVDPHDWWULEXWHVZLWKWKHH[FHSWLRQRIWKH
IROORZLQJ

7KHtreatment condition of interest ZLOOEHWKHFRPSDULVRQRIHSWLQH]XPDE PJWR
SODFHERZLWKRXWWKHXVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVDQGZLWK
RUZLWKRXWWKHXVHRISUHYHQWLYHPHGLFDWLRQIRUFOXVWHUKHDGDFKH
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
7KHHQGSRLQWVXVHGIRUWKHFRQWLQXRXVHQGSRLQWVDUHWKHIROORZLQJ

7KHendpoint to be obtained to address the clinical question LVWKHFKDQJHIURP%DVHOLQH
LQWKHQXPEHURIZHHNO\WLPHVDQDERUWLYHPHGLFDWLRQWULSWDQVRU 2ZDVXVHG
:HHNV 

7KHendpoint to be obtained to address the clinical question LVWKHFKDQJHIURP%DVHOLQH
LQWKHQXPEHURIGDLO\DWWDFNV'D\V

7KHendpoint to be obtained to address the clinical question LVWKHFKDQJHIURP%DVHOLQH
LQWKH QXPEHURIZHHNO\GD\VZLWKDWWDFNVSHUGD\:HHNV

7KHendpoint to be obtained to address the clinical question LVWKHQXPEHURIDWWDFNV
VWDUWLQJ KRXUVDIWHU WKHVWDUWRIWKHILUVWLQIXVLRQ
7KHFRQWLQXRXVNH\VHFRQGDU\HQGSRLQWV&KDQJHIURP%DVHOLQHLQWKH QXPEHURIZHHNO\
WLPHVDQDERUWLYHPHGLFDWLRQZDVXVHG:HHNV DQG&KDQJHIURP%DVHOLQHLQWKHQXPEHU
RIZHHNO\GD\VZLWKDWWDFNVSHUGD\:HHNV ZLOOEHDQDO\VHGXVLQJ DVLQJOH0050
PRGHO ZLWKRXWPXOWLSOHLPSXWDWLRQDVSUHVHQWHGLQVHFWLRQ RQSULPDU\DQDO\VLV XVLQJ
WKHEDVHOLQHYDOXHRIWKHYDULDEOHDVEDVHOLQH
7KH&KDQJHIURP%DVHOLQHLQWKHQXPEHURIGDLO\DWWDFNV'D\V ZLOOEHDQDO\VHGXVLQJ
DQDQDO\VLVRIFRYDULDQFH$1&29$ LQFOXGLQJWUHDWPHQWDQGFRXQWU\DVIDFWRUVDQGEDVHOLQH
QXPEHURIGDLO\DWWDFNVDVFRYDULDWH
7KH1XPEHURIDWWDFNVVWDUWLQJ KRXUVDIWHU WKHVWDUWRIWKHILUVWLQIXVLRQ RI,03ZLOOEH
DQDO\VHGXVLQJDQ$1&29$ ZLWKWUHDWPHQWDQGFRXQWU\DVIDFWRUVDQGZLWKWKH EDVHOLQH
QXPEHURIZHHNO\DWWDFNV DVFRYDULDWH
13.4.1.2 Response: 50% reduction from Baseline in the number of weekly attacks 
(Weeks 1-2)
7KHHVWLPDQGDWWULEXWHVDUHWKHIROORZLQJ

7KHtreatment condition of interest ZLOOEHWKHFRPSDULVRQRIHSWLQH]XPDE PJWR
SODFHERZLWKRXWWKHXVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVDQGZLWK
RUZLWKRXWWKHXVHRIDERUWLYH RUSUHYHQWLYHIRUFOXVWHUKHDGDFKH

7KHpopulation of interest ZLOOEHDOOSDWLHQWVZLWKHSLVRGLFFOXVWHUKHDGDFKHWKDWIXOILOWKH
LQFOXVLRQDQGH[FOXVLRQFULWHULD

7KHendpoint to be obtained to address the clinical question LVSDWLHQWVZLWK
UHGXFWLRQIURPEDVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV:HHNV

7KHintercurrent events: XVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVRU
LQWHUUXSWLRQRUSUHPDWXUHO\VWRSSLQJ,03LQIXVLRQZLOOEHDGGUHVVHGE\DWUHDWPHQWSROLF\
VWUDWHJ\

7KHpopulation level summary ZLOOEHWKHRGGVUDWLRIRUWKH HQGSRLQWEHWZHHQ
HSWLQH]XPDE PJDQGSODFHER
7KHSDWLHQWVZLWKUHGXFWLRQIURP%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV:HHNV
HQGSRLQW ZLOOEHDQDO\VHGXVLQJORJLVWLFUHJUHVVLRQZKHUHUHJLRQ DQGWUHDWPHQW DUH LQFOXGHGDV
IL[HGIDFWRUVDQGEDVHOLQHQXPEHURIZHHNO\DWWDFNVLVLQFOXGHGDVFRYDULDWH
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
13.4.1.3 Time from first infusion of IMP to resolution of cluster headache bout (within 
the first 4 weeks)
5HVROXWLRQLVGHILQHGDVWKHGD\DIWHUWKHODVWGD\ZLWKFOXVWHUKHDGDFKHDWWDFNVRIPRGHUDWH
VHYHUHRUH[FUXFLDWLQJ SDLQRUZKHUHDERUWLYHPHGLFDWLRQWULSWDQVRU 2ZDVXVHG
ZKLFKHYHULVWKHODWHVW ZKHQWKLVLVIROORZHGE\DZHHNSHULRGIUHHRIFOXVWHUKHDGDFKH
DWWDFNVRUZLWKFOXVWHUKHDGDFKHDWWDFNVZLWKRQO\PLOGSDLQQRWUHTXLULQJWKHXVHRIDERUWLYH
PHGLFDWLRQZKHUHERWKZHHNVLQWKHZHHNSHULRGKDGDWOHDVWGD\VRIH'LDU\FRPSOLDQFH
7KHZHHNSHULRGIUHHRIDWWDFNVRUZLWKRQO\PLOGSDLQRU1RSDLQ%DUHO\DQ\SDLQDUH
DOORZHGWRVWDUWRQDQ\GD\ZLWKLQWKHSHULRGDQGQRWFRQILQHGWR'D\'D\HWF 3DWLHQWV
WKDWGRQRWREWDLQUHVROXWLRQRIERXWDUHFHQVRUHGDWWKHODVWWLPHSRLQWWKDWLVIROORZHGE\
SHULRGVRIDZHHNHDFKZLWKDWOHDVWGD\VRIH'LDU\FRPSOLDQFH)RUWKHDQDO\VLVRIWLPHWR
UHVROXWLRQRIFOXVWHUKHDGDFKHERXWZLWKLQWKHILUVWZHHNVWKHODWHVWWLPH SRLQWIRUFHQVRULQJ
ZLOOEH'D\
7KHHVWLPDQGDWWULEXWHVDUHWKHIROORZLQJ

7KHtreatment condition of interest ZLOOEHWKHFRPSDULVRQRIHSWLQH]XPDE PJWR
SODFHERZLWKRXWWKHXVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVDQGZLWK
RUZLWKRXWWKHXVHRISUHYHQWLYH PHGLFDWLRQIRUFOXVWHUKHDGDFKH

7KHpopulation of interest ZLOOEHDOOSDWLHQWVZLWKHSLVRGLFFOXVWHUKHDGDFKHWKDWIXOILOWKH
LQFOXVLRQDQGH[FOXVLRQFULWHULD

7KHendpoint to be obtained to address the clinical question LVWLPHIURPILUVWLQIXVLRQ
WRUHVROXWLRQRIFOXVWHUKHDGDFKHERXWZLWKLQWKHILUVWZHHNV

7KHintercurrent events: XVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGV RU
LQWHUUXSWLRQRUSUHPDWXUHO\VWRSSLQJ,03LQIXVLRQZLOOEHDGGUHVVHGE\DWUHDWPHQWSROLF\
VWUDWHJ\

7KHpopulation level summary ZLOOEHWKHKD]DUG UDWLRIRUWKHHQGSRLQWEHWZHHQ
HSWLQH]XPDE PJDQGSODFHER
7LPHIURPLQIXVLRQWRUHVROXWLRQRIFOXVWHUKHDGDFKHERXWZLWKLQWKHILUVWZHHNVZLOOEH
DQDO\VHGXVLQJD&R[UHJUHVVLRQPRGHOZLWKEDVHOLQHQXPEHURIZHHNO\DWWDFNVDVFRYDULDWH
DQGWUHDWPHQWDQGOHQJWKRI6FUHHQLQJ3HULRG RUZHHNVRIVFUHHQLQJSHULRGDVIL[HG
IDFWRUV
13.4.2
Rationale for Selected Analysis Method for the Key Secondary Endpoints
7KH0050PRGHOLVFKRVHQDVLWLVDYHU\IOH[LEOHDQGUREXVWDQDO\VLVDQGZLWKWKHVHOHFWHG
H[SODQDWRU\YDULDEOHVLWZLOODOORZWUHDWPHQWWRYDU\IUHHO\E\ZHHNDFFRXQWIRUWKHEDVHOLQH
OHYHODQGIRUWKHVWUDWLILFDWLRQE\FRXQWU\DQGLQFOXGHWKHPRVWIOH[LEOHVWUXFWXUHIRUZLWKLQ
SDWLHQWYDULDWLRQ
7KHORJLVWLFUHJUHVVLRQPRGHOKDVEHHQFKRVHQIRULWVDELOLW\WRSURYLGHHVWLPDWHVRIWUHDWPHQW
HIIHFWVDVZHOODVDGMXVWIRUWKHHIIHFWVRIVWUDWDDQGFRYDULDWHV&RYDULDWHVDUHLQFOXGHGLQWKH
PRGHOEDVHGRQDQDSSURDFKLQFOXGLQJNH\IDFWRUVUHSUHVHQWLQJVWXG\GHVLJQIHDWXUHVVWUDWD
UHJLRQDQGWUHDWPHQWDQGEDVHOLQHQXPEHURIDWWDFNVWRDFFRXQWIRULWVSUHGLFWLYHDELOLW\
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
7KHFKRVHQFRYDULDWHDQGIL[HGIDFWRUVDUH FRQVLGHUHGWREHKLJKO\SUHGLFWLYHDQGWKXVWKH
ORJLVWLFUHJUHVVLRQPRGHOLVFRQVLGHUHGDVDSSURSULDWH
)RUWKHWLPH IURPLQIXVLRQ WRUHVROXWLRQNH\VHFRQGDU\HQGSRLQWWKHUDWLRQDOHIRUVHOHFWLQJ
&R[UHJUHVVLRQPRGHOLVWKDWLWLVDQDQDO\VLVIRU WLPHWRHYHQWHQGSRLQWV WKDWDOORZVIRU WKH
SRVVLELOLW\RIDGMXVWLQJ IRUFRYDULDWHV 7KHVHOHFWHGH[SODQDWRU\YDULDEOHVDUHH[SHFWHGWREH
UHOHYDQWSUHGLFWRUVRIUHVROXWLRQ
13.4.3
Sensitivity Analyses of the Key Secondary Endpoints
)RUHQGSRLQWVZKHUHGDWDLPSXWDWLRQLVXVHGWKHLPSDFWRIWKHLPSXWDWLRQVZLOOEHDVVHVVHGLQ
VHQVLWLYLW\DQDO\VHVDSSO\LQJGLIIHUHQWPHWKRGVRILPSXWDWLRQ
&KDQJHIURP%DVHOLQHLQWKHQXPEHURIZHHNO\GD\VZLWKDWWDFNVSHUGD\:HHNV
ZLOOEHDQDO\VHGXVLQJ WKHVDPHSULQFLSOHVIRUWKHS0,EXWZLWKDQHZVHHGDVSUHVHQWHGLQ
VHFWLRQ RQSULPDU\DQDO\VLVXVLQJWKHEDVHOLQHYDOXHRIWKHYDULDEOHDVEDVHOLQH
)RUWKHWLPHIURPLQIXVLRQWRUHVROXWLRQNH\VHFRQGDU\HQGSRLQWWKH&R[UHJUHVVLRQPRGHO
GHVFULEHGLQVHFWLRQ ZLOOEHUHSHDWHGZLWKVXUYLYDOGDWD JHQHUDWHGUHTXLULQJDWOHDVW
GD\VRIH'LDU\FRPSOLDQFHZLWKLQHDFKZHHN,QDGGLWLRQWKHDQDO\VLVZLOOEHUHSHDWHGXVLQJ
GDWDFHQVRUHG DWWKHGD\EHIRUHXVHRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGV
)RUWKHELQDU\UHVSRQVHNH\VHFRQGDU\ HQGSRLQWWKH ORJLVWLFUHJUHVVLRQPRGHOZLOOEHUXQRQ
GDWDZKHUHSDWLHQWVXVLQJWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVLVFRQVLGHUHG
DVQRQUHVSRQGHUV
,QDGGLWLRQWKHUHGXFWLRQIURP%DVHOLQHLQ WKH QXPEHURIZHHNO\DWWDFNV:HHNV
HQGSRLQWZLOOEHFDOFXODWHGIRUWKHGDWDVHWVJHQHUDWHGIRUWKHS0,DQDO\VLVIRUWKH
SULPDU\HQGSRLQWDQGDQDO\VHGXVLQJWKHVSHFLILHGORJLVWLFUHJUHVVLRQ7KHUHVXOWVZLOOEH
ZHLJKWHGWRJHWKHUXVLQJWKHDSSURDFKE\5DWLWFKHWDO
13.5 Analysis of the Secondary Endpoints
7KHFRQWLQXRXVVHFRQGDU\HQGSRLQWVZLWKWKHH[FHSWLRQRI3*,&+&58 DQG&KDQJHIURP
%DVHOLQHLQWKHGDLO\PHDQVFRUHRQSRLQWVHOIUDWLQJSDLQVHYHULW\VFDOH'D\VZLOOEH
DQDO\VHGXVLQJDQ 0050 PRGHOZLWKRXWPXOWLSOHLPSXWDWLRQVLPLODUWRWKHRQH GHVFULEHG
LQ WKHSULPDU\HQGSRLQW VHFWLRQ
7KH3*,&VFRUHZLOOEHDQDO\VHGXVLQJDQ 0050 ZLWKRXWPXOWLSOHLPSXWDWLRQZLWK
QXPEHURIDWWDFNVLQWKH6FUHHQLQJ3HULRG DVFRYDULDWHLQVWHDGRIEDVHOLQHVFRUH
7KH&KDQJHIURP%DVHOLQHLQWKHGDLO\PHDQVFRUHRQSRLQWVHOIUDWLQJSDLQVHYHULW\VFDOH
'D\V ZLOOEHDQDO\VHGXVLQJ DQ$1&29$ LQFOXGLQJWUHDWPHQWDQGFRXQWU\DVIDFWRUV
DQGEDVHOLQHDVFRYDULDWH
7DEOHVGLVSOD\LQJWKHFRXQWVDQGSHUFHQWDJHRIDQVZHUVWRHDFKFDWHJRU\RIUHVSRQVHRSWLRQV
IRUHDFKLWHPRI(4'/ZLOOEHSUHVHQWHGE\YLVLWDQGWUHDWPHQW)XUWKHUPRUHVKLIW WDEOHV
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
GLVSOD\LQJIRUHDFKLWHPLQ(4'/WKHQXPEHUDQGSHUFHQWDJHRISDWLHQWVZKR GHFUHDVHG
LQFUHDVHGRUKDGQRFKDQJHIURPEDVHOLQHLQWKHLWHPVFRUHZLOOEHSURYLGHGE\ YLVLWDQG
WUHDWPHQW
'HVFULSWLYHWDEOHVGLVSOD\LQJWKHGLVWULEXWLRQRIDQVZHUVWRWKHLWHPVLQ+&58DWHDFKYLVLW
ZLOOEHSURYLGHGE\WUHDWPHQW
'HVFULSWLYHWDEOHVGLVSOD\LQJWKHFRXQWVDQGSHUFHQWDJHRIWKHZHHNO\LQWHJUDWHGPHDVXUHRI
IUHTXHQF\DQGLQWHQVLW\RISDLQDWHDFKZHHNZLOOEHSURYLGHGE\WUHDWPHQW
7KHELQDU\VHFRQGDU\HQGSRLQWVUHVSRQVHZLOOEHDQDO\VHGLQDVLPLODUZD\DVIRUWKHNH\
VHFRQGDU\HQGSRLQWXVLQJDORJLVWLFUHJUHVVLRQZLWKUHJLRQ DQGWUHDWPHQWLQFOXGHGDVIL[HG
IDFWRUVDQGEDVHOLQHQXPEHURIZHHNO\DWWDFNVDVDFRYDULDWH
13.6 Analysis of the Exploratory Endpoints
7KHFRQWLQXRXVH[SORUDWRU\HQGSRLQWVZLOOEHDQDO\VHGXVLQJDQ 0050 ZLWKRXWPXOWLSOH
LPSXWDWLRQPRGHOVLPLODUWRWKHRQH GHVFULEHGLQ WKHSULPDU\HQGSRLQW VHFWLRQ
7KHELQDU\H[SORUDWRU\HQGSRLQWUHVSRQVHZLOOEHDQDO\VHGLQDVLPLODUZD\DVIRUWKHNH\
VHFRQGDU\HQGSRLQWXVLQJDORJLVWLFUHJUHVVLRQZLWKUHJLRQ DQGWUHDWPHQWLQFOXGHGDVIL[HG
IDFWRUVDQGEDVHOLQHQXPEHURIZHHNO\DWWDFNVDVDFRYDULDWH
$.DSODQ0HLHUSORWRIWLPHIURPLQIXVLRQWRUHVROXWLRQRIFOXVWHUERXWZLWKLQZHHNVZLOO
EHSURYLGHGIRUWKH PJ HSWLQH]XPDEWUHDWPHQW 6HHVHFWLRQ IRUGHWDLOVRQWKH
HQGSRLQW
7KH$1&29$PRGHOXVHGIRUDQDO\VLQJQXPEHURIDWWDFNVVWDUWLQJZLWKLQKRXUVRIWKH
VWDUWRIWKHILUVWLQIXVLRQGHVFULEHGLQVHFWLRQ ZLOOEHLPSOHPHQWHGIRUGDWDDVVHVVHG
LQ GLIIHUHQWWLPHLQWHUYDOVDIWHUWKHILUVWLQIXVLRQJLYLQJGLIIHUHQWWUHDWPHQWHVWLPDWHVRQH
IRUDWWDFNVVWDUWLQJKRXUVDIWHUWKHILUVWLQIXVLRQRQHIRUDWWDFNVVWDUWLQJKRXUVDIWHU
ILUVWLQIXVLRQDQGRQHIRUDWWDFNVVWDUWLQJKRXUVDIWHUWKHILUVWLQIXVLRQ
7KHIROORZLQJHQGSRLQWVZLOOEHSUHVHQWHGXVLQJGHVFULSWLYHVWDWLVWLFDODQDO\VHV

8VH\HVQRRIDERUWLYHPHGLFDWLRQWULSWDQVRU 2IRUHDFKRI:HHNV«

8VH\HVQRRISUHYHQWLYHPHGLFDWLRQIRUHDFKRI:HHNV«

8VH\HVQRRIWUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVIRUHDFKRI:HHNV
«

&KDQJHIURP%DVHOLQHLQWKH(4'/9LVXDO$QDORJXH6FDOH9$6VFRUHDW HDFKRI
:HHNVDQG

3DWLHQW*OREDO,PSUHVVLRQRI&KDQJH3*,&VFRUHDWHDFKRI:HHNVDQG

1XPEHURIZHHNO\DWWDFNVIRUHDFKRI:HHNV«

6HYHULW\RISDLQDYHUDJHSHUDWWDFNRYHUDZHHNEDVHGRQDSRLQWVHOIUDWLQJSDLQ
VHYHULW\VFDOHIRUHDFKRI:HHNV«
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
13.6.1
Covariate Investigation and Subgroup Analyses
7KHDVVXPSWLRQRIHTXDOWUHDWPHQWHIIHFWDFURVVVXEJURXSVZLOOEHLQYHVWLJDWHGRQDQ
H[SORUDWRU\EDVLVIRUDOOVXEJURXSVOLVWHGDERYHE\DGGLQJWKHWKUHHZD\LQWHUDFWLRQWHUP
VXEJURXSE\WUHDWPHQWE\ZHHNWRWKH0050PRGHO GHVFULEHGLQVHFWLRQ XVLQJ WKH
'36GDWD$WHVWIRUZKHWKHUWKHZD\LQWHUDFWLRQWHUPDQGWKHZD\LQWHUDFWLRQ
VXEJURXSE\WUHDWPHQWWHUPFDQEHUHPRYHGIURPWKH0050PRGHOZLOOEHSHUIRUPHGE\
FRPSDULQJWKHPRGHOZLWKRXWERWKWKHZD\LQWHUDFWLRQWHUPDQGWKHVXEJURXSE\WUHDWPHQW
ZD\LQWHUDFWLRQWHUPWRWKHPRGHOZLWKWKHZD\LQWHUDFWLRQWHUP
7KLVZLOOEHGRQHE\ILWWLQJERWKPRGHOVXVLQJPD[LPXPOLNHOLKRRG0/DQGPDNLQJD
OLNHOLKRRGUDWLRWHVWFRPSDULQJORJ4WRWKHDV\PSWRWLFȋ GLVWULEXWLRQZKHUH4LVWKH
TXRWLHQWRIWKHPD[LPLVHGOLNHOLKRRGIXQFWLRQV7KHSYDOXHIRUWKLVWHVWZLOOEHUHSRUWHG
$PRQJWKHVXEJURXSVWREHLQYHVWLJDWHGDUH

$JHFDWHJRU\!

$JHFDWHJRU\DWILUVWV\PSWRPVDQG!

3UHYLRXVWUHDWPHQWIDLOXUHV !

6H[

5DFH :KLWH2WKHU

5HJLRQ

%DVHOLQHVHYHULW\ EDVHOLQHDWWDFNV! EDVHOLQHDWWDFNV

'XUDWLRQRIWKH&+KLVWRU\WLPHVLQFHWKHILUVWV\PSWRPVRIWKHGLVHDVHDWVWXG\HQWU\
GHWHUPLQHGDW6FUHHQLQJ3HULRG  PHGLDQ!PHGLDQ

8VHRISUHYHQWLYHPHGLFDWLRQDWVWXG\VWDUW DW 6FUHHQLQJ3HULRG
7KHSULPDU\DQDO\VLVXVLQJS0, ZLOOEHUHSHDWHGIRUHDFKRIWKHVXEJURXSVPHQWLRQHGDERYH
EDVHGRQWKHVDPHLPSXWHGGDWDVHWV
14 Safety
14.1 Adverse Events
14.1.1
General Methodology for Adverse Events
$OOWKHWDEOHVDQGJUDSKVZLOOEHSUHVHQWHGE\WUHDWPHQW
7DEOHVE\SUHIHUUHGWHUPDQGWDEOHVE\V\VWHPRUJDQFODVV62&DQGSUHIHUUHGWHUPZLOOEH
VRUWHGLQGHVFHQGLQJRUGHUEDVHGRQWKHSHUFHQWDJHVRISDWLHQWVZLWKWKHVHDGYHUVHHYHQWVLQ
WKHHSWLQH]XPDE PJGRVHJURXS
8QOHVVRWKHUZLVHVSHFLILHGWKHVXPPDULHVRIDGYHUVHHYHQWVZLOOLQFOXGHWKHQXPEHUDQG
SHUFHQWDJHRISDWLHQWVZLWKDQDGYHUVHHYHQWDQGWKHWRWDOQXPEHURIHYHQWV
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
/LVWLQJVRIDGYHUVHHYHQWVZLOOEHVRUWHGE\VLWHWUHDWPHQWSDWLHQWVFUHHQLQJQXPEHUEDVHOLQH
ZHLJKWDJHVH[WUHDWPHQWSHULRGDQGDGYHUVHHYHQWVWDUWGDWHDQGLQFOXGHSUHIHUUHGWHUP
LQYHVWLJDWRUWHUPDGYHUVHHYHQWVWDUWGDWHDQGWLPHDQGSHULRG GD\VVLQFHILUVWGRVHRI,03
GDWHVWDUWWLPHVWRS RI,03'D\V VLQFHODVWVWDUWRI,03GXUDWLRQRIWKHDGYHUVHHYHQWGDWHRI
GHDWK LIDSSOLFDEOHDFWLRQWDNHQFDXVDOLW\LQWHQVLW\VHULRXVQHVVDQGRXWFRPH)RUDGYHUVH
HYHQWVWKDWFKDQJHLQLQWHQVLW\HDFKLQWHQVLW\ZLOOEHLQFOXGHG6WDUWDQGVWRSGDWHVLPSXWHGWR
GRFXPHQWFODVVLILFDWLRQRISDWLHQWVZLOOQRWEHGLVSOD\HGLQWKHOLVWLQJVRIDGYHUVHHYHQWV
14.1.2
Coding of Adverse Events
$GYHUVHHYHQWVZLOOEHFRGHGXVLQJ0HG'5$9HUVLRQRUODWHU
14.1.3
Classification of Adverse Events
$GYHUVHHYHQWVZLOOEHFODVVLILHGDFFRUGLQJWRWKHWLPHRIRQVHWRIWKHDGYHUVHHYHQW

pre-treatment adverse event ± DQDGYHUVHHYHQWWKDWVWDUWVRQRUDIWHUWKHGDWHWKHSDWLHQWUH
VLJQHGWKHInformed Consent Form DQGSULRUWRWKHGDWHDQGWLPHRIILUVWGRVHRI,03

treatment-emergent adverse event 7($(± DQDGYHUVHHYHQWWKDWVWDUWVGXULQJRUDIWHU
DGPLQLVWUDWLRQRIWKHILUVWGRVHRI,03RUDSUHWUHDWPHQWDGYHUVHHYHQWWKDWLQFUHDVHVLQ
LQWHQVLW\RUEHFRPHVVHULRXVGXULQJRUDIWHUDGPLQLVWUDWLRQRIWKHILUVWGRVHRI,03
)RUKDQGOLQJRIDGYHUVHHYHQWVZLWKLQFRPSOHWHVWDUWGDWHVWRIDFLOLWDWHWKLVFODVVLILFDWLRQ1RWH
WKDWIRUDQDGYHUVHHYHQWZLWKDQLQFRPSOHWHVWDUWGDWHRQO\WKHGDWHLWVHOIZLOOEHLPSXWHGDQG
XVHGIRUFODVVLILFDWLRQRIWUHDWPHQWHPHUJHQWVWDWXVLHWKHWLPHRIWKHLQIXVLRQZLOOQRWEH
WDNHQLQWRDFFRXQWZKHQFODVVLI\LQJDGYHUVHHYHQWVZLWKLQFRPSOHWHVWDUWGDWHVDQGWKXVVXFK
DQDGYHUVHHYHQWZLOOEHFODVVLILHGDVWUHDWPHQWHPHUJHQWVLPSO\LIWKHLPSXWHGVWDUWGDWHLVRQ
RUDIWHUWKHGDWHRIILUVW,03LQIXVLRQ
$QDGYHUVHHYHQWLVFRQVLGHUHGFDXVDOO\UHODWHGWRWKHXVHRIWKH,03ZKHQWKHFDXVDOLW\
DVVHVVPHQWE\WKHLQYHVWLJDWRULVprobable RUpossible
,IWKHFDXVDOLW\DVVHVVPHQWLVPLVVLQJWKHQWKH$(LVFRQVLGHUHGFDXVDOO\UHODWHG
14.1.4
Allocation of TEAEs to Treatment Periods
7($(VZLOOEHDOORFDWHGWRWUHDWPHQWSHULRGVDFFRUGLQJWRWKHWLPHRIRQVHWRIWKHDGYHUVH
HYHQW

TEAE in the 3ODFHERFRQWUROOHGPeriod ± D7($( WKDWVWDUWVRULQFUHDVHVLQLQWHQVLW\RU
EHFRPHVVHULRXVGXULQJ RUDIWHUWKHWLPHRILQIXVLRQRI,03LQWKH3ODFHERFRQWUROOHG
3HULRGDQGEHIRUHWKHGDWHDQGWLPHRIWKHLQIXVLRQRI,03LQWKH$FWLYH7UHDWPHQW3HULRG
)RUSDWLHQWVWKDWZHUHLQWKH3ODFHER&RQWUROOHG3HULRGZKHQUHFUXLWPHQWZDVVWRSSHGD
7($(LQWKH3ODFHER&RQWUROOHG3HULRGLVGHILQHGDVD7($( WKDWVWDUWVRULQFUHDVHVLQ
LQWHQVLW\RUEHFRPHVVHULRXVGXULQJ RUDIWHUWKHWLPHRILQIXVLRQ RI,03LQWKH3ODFHER
&RQWUROOHG3HULRGDQGEHIRUHWKHGDWHRIWKH:HHN9LVLW
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI

TEAE in the Delayed Start Period ± D7($( WKDWVWDUWVRULQFUHDVHVLQLQWHQVLW\RUEHFRPHV
VHULRXVGXULQJRUDIWHUWKHWLPHRI9LVLW,03LQIXVLRQ )RUSDWLHQWVWKDWZHUHLQWKH
3ODFHER&RQWUROOHG3HULRGZKHQUHFUXLWPHQWZDVVWRSSHGD7($(WKDWVWDUWVRULQFUHDVHV
LQLQWHQVLW\RUEHFRPHV VHULRXVDW RUDIWHUWKHGDWHRIWKH:HHN9LVLW
,IDQDGYHUVHHYHQWVWDUWVRQWKHGD\RIWKH9LVLW,03LQIXVLRQEXWZLWKDQXQNQRZQVWDUW
WLPHWKHDGYHUVHHYHQWZLOOEHFODVVLILHGDVWUHDWPHQWHPHUJHQWLQWKHSODFHERFRQWUROOHG
SHULRG
14.1.5
Presentation of Adverse Events
$OODGYHUVHHYHQWVZLOOEHOLVWHGIRUWKH$356LQFOXGLQJDIODJIRU7($(V
8QOHVVRWKHUZLVHVSHFLILHGDGYHUVHHYHQWV ZLOOEHUHSRUWHGIRUWKH3ODFHERFRQWUROOHG3HULRG
IRU$376DQGIRUWKH'HOD\HG6WDUW 3HULRG IRU$376B'6
)RUWKH3ODFHERFRQWUROOHG3HULRGDQGWKH'HOD\HG6WDUW 3HULRG DQRYHUYLHZRIWKH
SHUFHQWDJHVRISDWLHQWVZLWK7($(V7($(VOHDGLQJWRLQIXVLRQLQWHUUXSWLRQVHULRXVDGYHUVH
HYHQWV6$(VRUDGYHUVHHYHQWVOHDGLQJWRZLWKGUDZDODQGRISDWLHQWVZKRGLHGZLOOEH
SURYLGHG)RU7($(V6$(VDQGDGYHUVHHYHQWVOHDGLQJWRZLWKGUDZDODQG7($(VOHDGLQJ
WRLQIXVLRQLQWHUUXSWLRQWKHWRWDOQXPEHURIHYHQWVZLOOEHLQFOXGHG
14.1.6
Presentation of Pre-treatment Adverse Events
3UHWUHDWPHQWDGYHUVHHYHQWVZLOOEHVXPPDUL]HGE\SUHIHUUHGWHUPIRUWKH$376
14.1.7
Presentation of Treatment-emergent Adverse Events
7KHIROORZLQJVXPPDULHVZLOOEHSURYLGHGE\SHULRG

7($(VE\62&DQGSUHIHUUHGWHUP

7($(VE\SUHIHUUHGWHUP

7($(VE\VH[DQGSUHIHUUHGWHUP

7($(VZLWKDQLQFLGHQFH>LQDQ\WUHDWPHQW@E\SUHIHUUHGWHUP

FDXVDOO\UHODWHG7($(VE\62&DQGSUHIHUUHGWHUP

7($(VE\LQWHQVLW\mildmoderatesevere62&DQGSUHIHUUHGWHUP

FDXVDOO\UHODWHG7($(VE\LQWHQVLW\62&DQGSUHIHUUHGWHUP

7($(VRFFXUULQJRQWKHGD\RIGRVLQJDIWHULQIXVLRQVWDUWE\62&DQGSUHIHUUHGWHUPWKLV
LQFOXGHVGD\RI9IRUWKH3ODFHERFRQWUROOHG3HULRGDQGGD\RI9IRUWKH'HOD\HG6WDUW
3HULRG
14.1.8
Presentation of Deaths
$OOWKHDGYHUVHHYHQWVLQSDWLHQWVZKRGLHGZLOOEHOLVWHGIRUWKH$356
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
14.1.9
Presentation of Serious Adverse Events
$OOWKH6$(VZLOOEHOLVWHGIRUWKH$356
7UHDWPHQWHPHUJHQW6$(VZLOOEHVXPPDUL]HGE\

62&DQGSUHIHUUHGWHUP

SUHIHUUHGWHUP
14.1.10 Presentation of Adverse Events Leading to Withdrawal
$OOWKHDGYHUVHHYHQWVOHDGLQJWRZLWKGUDZDOZLOOEHOLVWHGIRUWKH$356
7($(VOHDGLQJWRZLWKGUDZDOZLOOEHVXPPDUL]HGE\

62&DQGSUHIHUUHGWHUP

SUHIHUUHGWHUP
14.1.11 Presentation of Adverse Events Leading to Study Drug Infusion Interruption
$OO$(VOHDGLQJWRVWXG\GUXJLQIXVLRQLQWHUUXSWLRQZLOOEHOLVWHGIRUWKH$356
7($(VOHDGLQJWRVWXG\GUXJLQIXVLRQLQWHUUXSWLRQZLOOEHVXPPDUL]HGIRUWKH3ODFHER
FRQWUROOHG3HULRGDQGIRUWKH'HOD\HG6WDUW3HULRGE\62&DQGSUHIHUUHGWHUP
14.1.12 Presentation of Adverse Events of Special Interest
7UHDWPHQWHPHUJHQWDGYHUVHHYHQWVRIVSHFLDOLQWHUHVW$(6,ZLOOFRQVLVWRIWKHSUHIHUUHG
WHUPVGHILQHGE\WKH604V+/7V+/*7VOLVWHGLQ 7DEOH
7KHIROORZLQJVXPPDULHVRIWUHDWPHQWHPHUJHQW$(6,VZLOOEHSURYLGHGIRUWKH3ODFHER
FRQWUROOHG3HULRGDQGIRUWKH'HOD\HG6WDUW3HULRG

$(6,VE\62&DQGSUHIHUUHGWHUP

$(6,VE\62&DQGSUHIHUUHGWHUPVHSDUDWHO\IRUHDFK LQGLYLGXDOHYHQWFDWHJRU\
14.2 General Methodology for Other Safety Data
8QOHVVRWKHUZLVHVSHFLILHGWDEOHVJUDSKVDQGOLVWLQJVZLOOEHEDVHGRQWKH$376 IRUWKH
3ODFHERFRQWUROOHG3HULRGDQGEDVHGRQWKH$376B'6IRUWKH'HOD\HG6WDUW3HULRG
)RUWKH3ODFHERFRQWUROOHG3HULRGGHVFULSWLYHVWDWLVWLFVIRUWKHVDIHW\YDULDEOHVERWKDEVROXWH
YDOXHVDQGFKDQJHVIURPEDVHOLQH9LVLWZLOOEHSUHVHQWHGE\YLVLW
)RUWKH'HOD\HG6WDUW 3HULRG GHVFULSWLYHVWDWLVWLFVIRUWKHVDIHW\YDULDEOHV ERWKDEVROXWH
YDOXHVDQGFKDQJHVIURP%DVHOLQH9LVLWDW:HHNZLOOEHSUHVHQWHGE\YLVLW
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
7KHQXPEHUDQGSHUFHQWDJHRISDWLHQWVZLWKDWOHDVWRQH3&6YDOXHDWDQ\SRVWEDVHOLQH
DVVHVVPHQWWLPHSRLQWZLOOEHVXPPDUL]HGE\YDULDEOH IRUWKH3ODFHERFRQWUROOHG3HULRGDQG
IRUWKH'HOD\HG6WDUW 3HULRG$OODYDLODEOHDVVHVVPHQWVZLOOEHLQFOXGHGLQWKHHYDOXDWLRQRI
3&6YDOXHV 3&6DVVHVVPHQWVIRUWKH'HOD\HG6WDUW3HULRGZLOOXVHWKHVWDUWRIWKH3ODFHER
FRQWUROOHG3HULRGDV%DVHOLQHIRUSDUDPHWHUVZKHUHWKH3&6FULWHULDLQYROYHVDFKDQJHIURP
%DVHOLQH
)RUSDWLHQWVZLWKSRVWEDVHOLQH3&6YDOXHVOLVWLQJVZLOOEHSURYLGHGLQFOXGLQJDOOWKHYDOXHV
IRUWKRVHSDWLHQWVIRUWKHYDULDEOHE\WUHDWPHQWSHULRGZLWKIODJJLQJRI3&6YDOXHV
)RUSDUDPHWHUVZKHUHWKH3&6GHFLVLRQLVEDVHGXSRQDFRPSDULVRQZLWKEDVHOLQHWKHYLVLW
ZLOOEHXVHGDVEDVHOLQH
14.3 Clinical Safety Laboratory Test Data
14.3.1
Data Presentation
7KH3&6FULWHULDXVHGIRUWKHFOLQLFDOVDIHW\ODERUDWRU\DUHWKH/XQGEHFNVWDQGDUG3&6FULWHULD
GHVFULEHGLQ623BGPV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studiesYHUVLRQDQGDUHDOVRLQFOXGHGLQ
7DEOH
7KHFOLQLFDOVDIHW\ODERUDWRU\WHVWYDOXHVZLOOEHSUHVHQWHGLQERWKFRQYHQWLRQDODQG 6\VWqPH
,QWHUQDWLRQDO6,XQLWV
)RUXULQHGLSVWLFNVIRUZKLFKWKHUHVXOWVDUHFDWHJRULFDOYDOXHVIRUH[DPSOHQHJDWLYHWUDFH
WKHQXPEHUDQGSHUFHQWDJHRI SDWLHQWVZLOOEHVXPPDULVHGIRUHDFKWHVWE\YLVLW
7KHPLFURVFRS\UHVXOWVZLOOEHOLVWHGIRUSDWLHQWVZLWKILQGLQJVE\DVVHVVPHQWWLPHSRLQW
14.3.2
Potential Drug-induced Liver Injury (DILI)
6LJQDOVRI',/,ZLOOEHDVVHVVHGDFFRUGLQJWRWKH)'$JXLGHOLQH XVLQJWKHIROORZLQJFULWHULD

$/7RU$67!î!î!î!îRU!î8/1

WRWDOELOLUXELQ%,/,!î8/1

DONDOLQHSKRVSKDWDVH$/3!î8/1

$/7RU$67!î8/1$1'WRWDOELOLUXELQ!îRU!î8/1
3DWLHQWVIXOILOOLQJDQ\RIWKHFULWHULDZLOOEHOLVWHGDQGWKH OLVWLQJZLOOLQFOXGHDOOWKH$/7
$67%,/,DQG$/3YDOXHVIRUWKRVHSDWLHQWVVRUWHGE\DVVHVVPHQWGDWHDQGWLPHLQ
DVFHQGLQJRUGHU,IDFULWHULRQIRUDWHVWLVIXOILOOHGWKHYDOXHZLOOEHIODJJHGZLWKWKHKLJKHVW
FULWHULRQIXOILOOHGIRUH[DPSOH$67 !î8/1!î8/1!î8/1RU!î8/1
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
,QDGGLWLRQDVVHVVPHQWWLPHSRLQWVIRUSDWLHQWVIRUZKRP+\¶V/DZLVSRWHQWLDOO\IXOILOOHG
ZLOODOVREHIODJJHGLQWKHOLVWLQJS+</

$/7RU$67!î8/1$1'

DONDOLQHSKRVSKDWDVHî8/1$1'

WRWDOELOLUXELQî8/1
7KHQXPEHURISDWLHQWVZKRPHWDQ\RIWKHFULWHULDVSHFLILHGDERYHDWDQ\SRVWEDVHOLQHYLVLW
ZLOOEHVXPPDUL]HGE\DFWXDOWUHDWPHQW DQGSHULRG,QWKHVXPPDULHVHDFKSDWLHQWZLOOEH
FRXQWHGRQO\RQFHXVLQJWKHPD[LPXPDVVHVVPHQWRUWKHPRVWVHYHUHIRUWKHFRPELQHG
FULWHULD7KHVXPPDULHVZLOODOVRLQFOXGHWKHQXPEHURISRWHQWLDO+\¶V/DZFDVHV
14.4 Vital Signs and Weight
7KH3&6FULWHULDXVHGIRUYLWDOVLJQVDQGZHLJKWDUHWKH/XQGEHFNVWDQGDUG3&6FULWHULD
GHVFULEHGLQ623BGPV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studiesYHUVLRQDQGDUHDOVRLQFOXGHGLQ
7DEOH
14.5 ECGs
7KH3&6FULWHULDXVHGIRUWKH(&*SDUDPHWHUVDUHWKH/XQGEHFNVWDQGDUG3&6FULWHULD
GHVFULEHGLQ623BGPV – PCS and standard reference values for laboratory 
investigations, vital signs and ECGs in clinical studiesYHUVLRQDQGDUHDOVRLQFOXGHGLQ
7DEOH
,QDGGLWLRQWR WKHWDEOHVDQGOLVWLQJVVSHFLILHGLQVHFWLRQ  DEVROXWHYDOXHVDQGFKDQJHV
IURP%DVHOLQH9LVLWLQ47F)ZLOODOVREHVXPPDUL]HGFDWHJRULFDOO\E\YLVLWDQGWUHDWPHQW
VHSDUDWHO\IRUWKH3ODFHERFRQWUROOHG3HULRG7KHFDWHJRULHVWKDWZLOOEHXVHGDUHDVIROORZV
IRUWKHDEVROXWH47F)YDOXHV

47F)LQWHUYDOPVHF

47F)LQWHUYDO PVHF

47F)LQWHUYDO! PVHF

47F)LQWHUYDO!PVHF
7KHFDWHJRULHVWKDWZLOOEHXVHGIRUWKHFKDQJHIURPEDVHOLQH47F)YDOXHVDUH

47F)LQWHUYDOLQFUHDVHIURPEDVHOLQH!PVHF

47F)LQWHUYDOLQFUHDVHIURPEDVHOLQH!PVHF
)XUWKHUPRUHWKHQXPEHUDQGSHUFHQWDJHRISDWLHQWVEHLQJFODVVLILHGDVKDYLQJHLWKHUD
QRUPDODEQRUPDOEXWQRWFOLQLFDOO\VLJQLILFDQWDEQRUPDODQGFOLQLFDOO\VLJQLILFDQWRUQRW
LQWHUSUHWDEOH(&*UHVXOWEDVHGRQWKHRYHUDOOLQWHUSUHWDWLRQRIWKH(&*IURPWKHLQYHVWLJDWRU
ZLOOEHVXPPDUL]HGE\YLVLWDQGWUHDWPHQWVHSDUDWHO\IRUHDFKSHULRG
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
14.6 Other Safety Endpoints
14.6.1
Columbia-Suicide Severity Rating Scale (C-SSRS) Scores
7KH&6656ZDVDGPLQLVWHUHG

IRUOLIHWLPHXVLQJWKHBaselineScreening Version± WKH&6656DVVHVVPHQWDWVFUHHQLQJ
9LVLWWKDWFROOHFWVDOLIHWLPHUHFDOO

IRUWKHSDVWPRQWKDWVFUHHQLQJXVLQJWKHBaselineScreening Version± WKH&6656
DVVHVVPHQWDWVFUHHQLQJ9LVLWWKDWIRFXVHVRQWKHODVWPRQWK

DWEDVHOLQHXVLQJWKHSince Last Visit Version± WKH&6656DVVHVVPHQWDWEDVHOLQHWKDW
FROOHFWVLQIRUPDWLRQVLQFHWKHSUHYLRXVYLVLW

SRVWEDVHOLQHXVLQJWKHSince Last Visit Version± WKH&6656DVVHVVPHQWVDIWHUEDVHOLQH
7KHQXPEHUVDQGSHUFHQWDJHVRISDWLHQWVZLWKOLIHWLPHSDVWPRQWKEDVHOLQHRUSRVW
EDVHOLQHLGHDWLRQVRUEHKDYLRXUVEDVHGRQWKH&6656ZLOOEHVXPPDUL]HGE\WUHDWPHQW)RU
HDFKVXPPDU\WKHPRVWVHYHUHLWHPZLWKDQDQVZHU³<HV´IRUHDFKSDWLHQW DFFRUGLQJWRWKH
RUGHULQJJLYHQLQ3DQHO LVGLVSOD\HG)RUWKHSRVWEDVHOLQH DVVHVVPHQWVWKHVXPPDULHVZLOO
EHE\WUHDWPHQW DQGSHULRG
7KHQXPEHUDQGSHUFHQWDJHRISDWLHQWVZLWKno suicidal ideation or behaviour ZLOOEH
LQFOXGHGLQWKHVXPPDULHV
Panel 2
C-SSRS Scores
C-SSRS Score
Related to:

:LVKWREHGHDG
6XLFLGDOLGHDWLRQ

1RQVSHFLILFDFWLYHVXLFLGDOWKRXJKWV

$FWLYHVXLFLGDOLGHDWLRQZLWKDQ\PHWKRGVQRWSODQZLWKRXWLQWHQWWRDFW

$FWLYHVXLFLGDOLGHDWLRQZLWKVRPHLQWHQWWRDFWZLWKRXWVSHFLILFSODQ

$FWLYHVXLFLGDOLGHDWLRQZLWKVSHFLILFSODQDQGLQWHQW

3UHSDUDWRU\DFWVRUEHKDYLRXU
6XLFLGDOEHKDYLRXU

$ERUWHGDWWHPSW

,QWHUUXSWHGDWWHPSW

1RQIDWDOVXLFLGHDWWHPSW

&RPSOHWHGVXLFLGHRQO\DSSOLFDEOHIRUWKHSRVWEDVHOLQHDVVHVVPHQWV
0LVVLQJ&6656VFRUHVZLOOQRWEHLPSXWHG
3RVLWLYHUHVSRQVHVWRnon-suicidal self-injurious behaviour ZLOOEHVXPPDUL]HGVHSDUDWHO\
)RUSDWLHQWVZLWKDQ\SRVWEDVHOLQH VXLFLGDOLGHDWLRQRUEHKDYLRXU&6656VFRUHVRI WR
OLVWLQJVZLOOEHSURYLGHGLQFOXGLQJDOO&6656VFRUHVIRUWKRVHSDWLHQWV
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
15 Immunogenicity
)RUVXEMHFWVZLWKSUHH[LVWLQJDQWLERGLHVDWEDVHOLQHWKHQXPEHUDQGSHUFHQWRIVXEMHFWVZKR
DUHSRVLWLYHIRUDQWLHSWLQH]XPDEDQWLERG\ZLOOEHVXPPDUL]HGDWEDVHOLQH7KHQXPEHUDQG
SHUFHQWDJH RIVXEMHFWVZKRGHYHORSDQWLGUXJDQWLERGLHVWRHSWLQH]XPDEGXULQJWKHWULDOZLOO
EHVXPPDUL]HGE\YLVLW 'HQRPLQDWRUVIRUSHUFHQWDJHVZLOOEHWKHWRWDOQXPEHURIVDPSOHV
WDNHQIRUWKHYLVLW3DWLHQWVZLWKQHXWUDOL]LQJDQWLHSWLQH]XPDEDQWLERGLHVZLOODOVREH
VXPPDUL]HGE\YLVLW
6XEMHFWVZLWKDSRVLWLYHDQWLHSWLQH]XPDEDQWLERG\UHVXOW$'$1$EZLOOEHOLVWHGWRJHWKHU
ZLWKVLWHWUHDWPHQWSDWLHQWVFUHHQLQJQXPEHUDJHZHLJKWVH[DQGYLVLW
6XPPDULHV RI7($(VE\62&DQGSUHIHUUHGWHUPIRUSDWLHQWVZKRDUH$'$SRVLWLYHZLOOEH
SURYLGHGIRUWKH SHULRGIURPEDVHOLQHDQGXQWLOWKH6DIHW\)ROORZXS 9LVLW
,QDGGLWLRQVXPPDULHVRI7($(VRI+\SHUVHQVLWLYLW\DQG$QDSK\ODFWLF5HDFWLRQVE\62&
DQGSUHIHUUHGWHUPIRUSDWLHQWVZKRDUH$'$SRVLWLYHZLOOEHSURYLGHGIRUWKHSHULRGIURP
EDVHOLQHDQGXQWLOWKH6DIHW\)ROORZXS9LVLW
6XEMHFWVZLWKDSRVLWLYH$'$DQGDGYHUVHHYHQWVRFFXUULQJDIWHUVWDUWRI9LVLW,03LQIXVLRQ
ZLOOEHOLVWHG7KHOLVWLQJZLOOLQFOXGHWKH$'$UHVXOWWKHDVVHVVPHQWGDWHWKHSUHIHUUHGWHUP
IRUWKHDGYHUVHHYHQWDQGVWDUWGDWHDQGVWRSGDWHRIWKHDGYHUVHHYHQW7KH$'$UHVXOWVDQG
DGYHUVHHYHQWVZLOOEHOLVWHGLQFKURQRORJLFDORUGHUDFFRUGLQJWRDVVHVVPHQWGDWH DQGWKHVWDUW
GDWHRIWKHDGYHUVHHYHQW
,IDSSURSULDWHGDWDZLOOEHVXPPDUL]HGRUOLVWHGIRU

7LWHUUDQJHPHGLDQDQGLQWHUTXDUWLOHUDQJH,45IRUVXEMHFWVZLWKSUHH[LVWLQJDQWLERGLHV
DWEDVHOLQHDQGIRUVXEMHFWVWKDWDUH$'$SRVLWLYHDW:HHN

)RU VXEMHFWVZLWKSUHH[LVWLQJDQWLERGLHVDWEDVHOLQHWKHUDWLRRI:HHNWLWHUWRWKH
EDVHOLQHWLWHU

0HDQH[SRVXUHIRUVXEMHFWWKDWDUH$'$SRVLWLYHDW:HHN
$OOLPPXQRJHQLFLW\GDWDZLOOEHOLVWHGE\VXEMHFWDQGSHULRG
16 Pharmacokinetic/Pharmacodynamic Analyses
$VHSDUDWHDQDO\VLVSODQIRUSKDUPDFRNLQHWLFSKDUPDFRG\QDPLFDQDO\VHVZLOOEHSUHSDUHGE\
4XDQWLWDWLYH3KDUPDFRORJ\+ /XQGEHFN $6 7KH3.3'DQDO\VLVSODQZLOOEHILQDOL]HG
EHIRUHXQEOLQGLQJGDWDGHOLYHU\RISODVPDFRQFHQWUDWLRQV
17 Blinded Data Reviews
7KHTXDOLW\RIWKHVWXG\ZLOOEHRYHUVHHQE\SHUIRUPLQJEOLQGHGGDWDUHYLHZVGXULQJWKH
FRQGXFWRIWKHVWXG\7KHUHYLHZVPD\LQFOXGHEXWDUHQRWOLPLWHGWRGDWDTXDOLW\SURWRFRO
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
DGKHUHQFHDQGWKHDSSURSULDWHQHVV RIGHVLJQDVVXPSWLRQVLQFOXGLQJWKHVDPSOHVL]H
DVVXPSWLRQV
18 Interim Analyses
$QLQWHULPIXWLOLW\DQDO\VLVZLOOEHSHUIRUPHGEDVHGRQUDQGRPL]HGDQGWUHDWHGSDWLHQWV
ZKRKDYHKDGWKHFKDQFHRIFRPSOHWLQJWKH:HHN9LVLWWRDOORZIRUVWRSSLQJWKHVWXG\
IRUIXWLOLW\LIWKHOHYHORIHIILFDF\LVFRQVLGHUDEO\ORZHUWKDQH[SHFWHG,IWKHHVWLPDWHG
WUHDWPHQWHIIHFWIRUWKHSULPDU\HQGSRLQWLVOHVVWKDQRIWKHH[SHFWHGHIIHFWVL]H 
/XQGEHFNPD\GHFLGHWRVWRSWKHVWXG\IRUIXWLOLW\
:KHQWKHSDWLHQWVKDYHKDGWKHFKDQFHRIKDYLQJWKH:HHN YLVLW 9LVLWWKHGDWDZLOOEH
FOHDQHGDQGVHQGWRDQLQGHSHQGHQW&52%LRVWDWDDVZHOODVWUHDWPHQWFRGHVDQGWKH
LQGHSHQGHQW&52ZLOOXQEOLQGWKHGDWDDQGSHUIRUPWKHLQWHULPDQDO\VLV/XQGEHFNDQGWKH
&52FRQGXFWLQJWKHVWXG\ZLOOUHPDLQEOLQGHG
7KHLQWHULPDQDO\VLVZLOOEHEDVHGRQWKHSULPDU\DQDO\VLV SHUIRUPHGE\WKHLQGHSHQGHQW
&52DQDO\VLQJWKHFKDQJHIURP%DVHOLQHLQ WKH QXPEHURIZHHNO\DWWDFNV:HHNV
7KHLQGHSHQGHQW&52ZLOOLQIRUPDSUHGHILQHGJURXSRI/XQGEHFNHPSOR\HHVZKHWKHUWKH
FULWHULRQIRUWKHLQWHULPIXWLOLW\KDYHEHHQPHWRUQRWWKLVZLOOEHGHVFULEHGPRUHWKRURXJKO\
LQDQ,QWHULP&KDUWHU1RIXUWKHUGHWDLOVRIWKHLQWHULPDQDO\VLVUHVXOWVZLOOEHSURYLGHGWR
/XQGEHFN/XQGEHFNPD\GHFLGHWRVWRSWKHVWXG\IRUIXWLOLW\RUFRQWLQXHWKHHQUROPHQW
5HFUXLWPHQWFRQWLQXHVZKLOHWKHLQWHULPDQDO\VLVLVFRQGXFWHG
'HWDLOVRIWKHVWDWLVWLFDODQDO\VLVIRUWKHLQWHULPDQDO\VLVZLOOEHGHVFULEHGLQDQ,QWHULP
6WDWLVWLFDO$QDO\VLV3ODQ
19 Sample Size Considerations
*RDGVE\ GHVFULEHVDVWXG\LQH&+ZKHUHWKHILUVWZHHNVKDYHDGHVLJQVLPLODUWR
WKLVVWXG\7KHGLIIHUHQFHEHWZHHQJDOFDQH]XPDEDQGSODFHERLQFKDQJHIURPEDVHOLQHLQ
ZHHNO\IUHTXHQF\RIDWWDFNVDW:HHNLVHVWLPDWHGDWDWWDFNVDQGDW:HHNLVHVWLPDWHG
DWDWWDFNV7KHDYHUDJHGLIIHUHQFHWRSODFHERDFURVV:HHNDQG:HHNLVHVWLPDWHGDW
%DVHGRQWKH&,SUHVHQWHGLQWKHSXEOLFDWLRQWKH6'DW:HHNLVHVWLPDWHGDWDQGWKH
6'DW:HHNLVHVWLPDWHGDW$VVXPLQJWKDWWKHFRUUHODWLRQEHWZHHQ:HHNDQG:HHN
 LVWKH6'IRUWKHDYHUDJHRI:HHNDQGZLOOEH6' 
$VVXPLQJDGLIIHUHQFHRIHSWLQH]XPDEWRSODFHERRIDWWDFNVZLWKDQ6' 
SDWLHQWVSHUWUHDWPHQWZLOOSURYLGHSRZHUIRUVHHLQJDQHIIHFWXVLQJDWZRVLGHG
VLJQLILFDQFHOHYHO
6LQFHWKHHVWLPDWHGWUHDWPHQWGLIIHUHQFHPD\EHVOLJKWO\GHFUHDVHGGXHWRWKHXVHRIS0,DQ
DGGLWLRQDORISDWLHQWVKDYHEHHQDGGHG7KLV\LHOGVDWRWDORISDWLHQWSHUWUHDWPHQW
VHTXHQFH
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
20 Statistical Software
7KHVWDWLVWLFDOVRIWZDUHXVHGZLOOEH6$69HUVLRQRUODWHU
21 Changes to Analyses Specified in the Protocol
1$
22 Changes compared to version 1 of the SAP
$IWHUWKHLQWHULPUHVXOWDQGWKHGDWDEDVHUHOHDVHDQGKHDGOLQHUHVXOWVIRUWKH3ODFHER
FRQWUROOHG3HULRGZHUHDYDLODEOH WKH6$3KDVEHHQXSGDWHGWRUHIOHFWWKHIROORZLQJFKDQJHV

)RUSDWLHQWVWKDWZHUHLQWKH3ODFHERFRQWUROOHG3HULRGZKHQUHFUXLWPHQWZDVVWRSSHGLW
KDVEHHQFODULILHGKRZWKH\ZHUHDVVLJQHGWRWKH'HOD\HG6WDUWSHULRGVLQFHLWZDVQRW
SRVVLEOHWRXVHWKHWLPLQJRIWKHVHFRQGLQIXVLRQRI,03DVWKHGHOLPLWHUEHWZHHQ3ODFHER
FRQWUROOHGDQG'HOD\HG6WDUW3HULRGVIRUWKHVHSDWLHQWV

)RUWKHNH\VHFRQGDU\HQGSRLQW³7LPHIURPILUVWLQIXVLRQRI,03WRUHVROXWLRQRIFOXVWHU
KHDGDFKHERXWZLWKLQWKHILUVWZHHNV´LWKDVEHHQFODULILHGKRZWRFDOFXODWHWKHWLPHIRU
FHQVRUHGREVHUYDWLRQV

7KHDOOSDWLHQWVWUHDWHGLQ'HOD\HG6WDUW3HULRGVHW$376B'6KDVEHHQDGGHGWRFODULI\
ZKDWSDWLHQWVDUHLQFOXGHGLQWKHVDIHW\DQDO\VHVIRUWKH'HOD\HG6WDUW3HULRG
Panel 3
Changes to the SAP from Edition 1.0 to 2.0
Section 
Number Section Title
Change / Rationale for Change






6WXG\'HVLJQ
'HILQLWLRQRI3HULRGV
'HILQLWLRQRI:LWKGUDZDO
'HILQLWLRQRI3ODQQHG
YHUVXV$FWXDO7UHDWPHQW
5HFHQWDQG&RQFRPLWDQW
0HGLFDWLRQ
$OORFDWLRQRI7($(VWR
7UHDWPHQW3HULRGV
Added7H[WKDVEHHQDGGHGLQDOOWKHVHVHFWLRQVWRFODULI\KRZWR
DGGUHVVSDWLHQWVWKDWZHUHLQWKH3ODFHERFRQWUROOHG3HULRGZKHQLW
ZDVGHFLGHGWRVWRSUHFUXLWPHQW

7LPHIURPILUVWLQIXVLRQRI
,03WRUHVROXWLRQRIFOXVWHU
KHDGDFKHERXWZLWKLQWKH
ILUVWZHHNV
Added7H[WKDVEHHQDGGHGWRFODULI\KRZWRFDOFXODWHWKHWLPHZKHQ
UHVROXWLRQZDVQRWREWDLQHG
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Section 
Number Section Title
Change / Rationale for Change








$QDO\VLV6HWV
6XPPDU\RI3DWLHQW
'LVSRVLWLRQ
3UHVHQWDWLRQRI$GYHUVH
(YHQWV
3UHVHQWDWLRQRI7UHDWPHQW
(PHUJHQW$GYHUVH(YHQWV
3UHVHQWDWLRQRI6HULRXV
$GYHUVH(YHQWV
3UHVHQWDWLRQRI$GYHUVH
(YHQWV/HDGLQJWR6WXG\
'UXJ,QIXVLRQ,QWHUUXSWLRQ
3UHVHQWDWLRQRI$GYHUVH
(YHQWVRI6SHFLDO,QWHUHVW
*HQHUDO0HWKRGRORJ\IRU
2WKHU6DIHW\ 'DWD
Added/Updated7H[WKDVEHHQDGGHGWRGHVFULEHWKH$376B'6GDWD
VHWDQGXSGDWHGWRFODULI\ZKHQWKLVGDWDVHWZLOOEHDSSOLHG

*HQHUDO0HWKRGRORJ\IRU
2WKHU6DIHW\'DWD
Updated: ,WKDVEHHQFODULILHGWKDWDOOFKDQJHVZLOOEHVHHQLQ
FRPSDULVRQWR%DVHOLQH:HHN
23 Details on Data Handling
23.1 Derived Variables
23.1.1
eDiary
7KHGDWDEDVHGRQWKHH'LDU\ZLOOEHVXPPDULVHGZHHNO\7KHSRVWEDVHOLQHZHHNO\LQWHUYDOV
VWDUWZLWKWKHGD\DIWHUWKHILUVWLQIXVLRQ'D\DQGWKHQFRXQW'D\WR'D\DVWKHILUVW
ZHHNDQGFRQWLQXHZLWKGD\ZHHNVIURPWKHUH
'D\VZKHUHWKHH'LDU\LVFRPSOHWHGDUHGD\VZKHUH DWOHDVWRQHFOXVWHUKHDGDFKHZHUH
UHFRUGHGLQWKHFOXVWHUKHDGDFKHH'LDU\RULWZDVFRQILUPHGLQWKHHYHQLQJH'LDU\WKDWQR
FOXVWHUKHDGDFKHVKDGWDNHQSODFHGXULQJWKDWGD\
,QFDVHRIDUHSRUWLQJGD\ZKHUHDSDWLHQWDQVZHUVLQWKHHYHQLQJGLDU\WKDWWKH\H[SHULHQFHGD
FOXVWHUKHDGDFKH RQWKDWGD\EXWWKH SDWLHQW QHYHUUHFRUGV DQDFWXDOFOXVWHUKHDGDFKHLQWKH
FOXVWHUKHDGDFKHH'LDU\WKHGD\ZLOOEHDVVLJQHGDVGD\ZKHUHWKHH'LDU\KDVQRWEHHQ
FRPSOHWHGDQGLPSXWDWLRQUXOHVDVVSHFLILHGEHORZZLOOEHDSSOLHG
23.1.1.1 Imputation of missing baseline assessments
7KHEDVHOLQHDVVHVVPHQWV XVHWKH H'LDU\GDWDFROOHFWHGLQWKH6FUHHQLQJ3HULRG,QFDVHRI
H[WHQVLRQRI6FUHHQLQJ3HULRGWKHEDVHOLQHDVVHVVPHQWVZLOOEH EDVHGRQWKHILUVWGD\VLQ
WKHH[WHQVLRQRI6FUHHQLQJ3HULRGDQGZLWKQRH[WHQVLRQRI6FUHHQLQJ3HULRG WKHEDVHOLQH
DVVHVVPHQWVZLOOEH EDVHGRQWKHILUVWGD\VLQVFUHHQLQJSHULRG,IWKHH'LDU\LVFRPSOHWHG
RQDWOHDVWRXWRIWKHGD\VWKHEDVHOLQHDVVHVVPHQWVZLOOEHFDOFXODWHGXVLQJSURUDWLQJ
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
7KHEDVHOLQHQXPEHURIZHHNO\DWWDFNVZLOOEHFDOFXODWHG DVIROORZV
7*(Reported number of attacks/Reported eDiary Days)
)RUSDWLHQWVZLWKGD\VZLWKREVHUYDWLRQVGXULQJWKH%DVHOLQH3HULRGWKHPLVVLQJEDVHOLQH
QXPEHURIZHHNO\DWWDFNVZLOOEHGUDZQIURPDQRUPDOGLVWULEXWLRQZLWKWKHPHDQDQG6'
WDNHQIURPWKHEDVHOLQHQXPEHURIZHHNO\DWWDFNVIRUSDWLHQWVZKHUHDEDVHOLQHQXPEHURI
ZHHNO\DWWDFNVKDVEHHQREWDLQHGIURPSDWLHQWVZLWKDWOHDVWRIGD\VRIREVHUYDWLRQVDQG
SRVVLEO\XVLQJSURUDWLQJIRUWKHFDOFXODWLRQ,IQHHGHGWKLVVWHSZLOOEHLQFRUSRUDWHGDVWKH
LQLWLDOVWHSRIWKHS0,DQDO\VLVDQGWKXVQHZUDQGRPEDVHOLQHYDOXHVZLOOEHGUDZQIRUHDFK
RIWKHVLPXODWHGGDWDVHWVLQFDVHRIPLVVLQJEDVHOLQHYDOXHV
)RUWKHHQGSRLQW&KDQJHIURP%DVHOLQHLQQXPEHURI'DLO\DWWDFNV'D\VWKHEDVHOLQH
QXPEHURIGDLO\DWWDFNVZLOOEHFDOFXODWHGDVEDVHOLQHQXPEHURIZHHNO\DWWDFNV GLYLGHGE\
23.1.1.2 Imputation of missing post-baseline eDiary assessments
)RUGD\ZHHNO\SHULRGVZKHUHWKHH'LDU\LVFRPSOHWHGRQDWOHDVWRXWRIWKHGD\V
SURUDWLQJZLOOEHXVHGZKHUHGD\VZLWKPLVVLQJLQIRUPDWLRQDUHLPSXWHGE\WKHREVHUYHG
PHDQQXPEHURIDWWDFNVLQWKHGD\ZHHNDVIROORZV
7*(Reported number of attacks/Reported eDiary Days)
)RUGD\ZHHNO\SHULRGVZKHUHWKHH'LDU\LVFRPSOHWHGRQGD\VRUOHVVWKHGD\ZHHNO\
REVHUYDWLRQZLOOEHVHWWRPLVVLQJ
)RUVLPLODUHQGSRLQWVEDVHGRQLQIRUPDWLRQIURPWKHH'LDU\&OXVWHUKHDGDFKHDQGHYHQLQJ
H'LDU\FRPELQHGLQWRGD\ZHHNO\SHULRGVSURUDWLQJDVGHVFULEHGDERYHZLOOEHXVHGZKHQ
WKHH'LDU\KDVEHHQFRPSOHWHGIRUDWOHDVWGD\VDQGWKHZHHNO\REVHUYDWLRQ ZLOOEHVHWWR
PLVVLQJZKHQWKHH'LDU\KDVEHHQFRPSOHWHGIRUGD\VRUOHVV
7KHQXPEHURIGDLO\DWWDFNV'D\VZLOOEHFDOFXODWHGDVIROORZVLIWKHH'DLU\KDVEHHQ
FRPSOHWHGIRUDWOHDVWRIWKHGD\V'D\'D\DQG'D\
Reported number of attacks/Reported eDiary Days
)RUQXPEHURIDWWDFNVVWDUWLQJZLWKLQKRXUVRIWKHVWDUWRIWKHILUVWLQIXVLRQQRLPSXWDWLRQ
RIGDWDZLOOEHGRQHDQGWKHHQGSRLQWZLOORQO\EHFDOFXODWHGLIWKHUHDUHGDWDDYDLODEOHIURP
ERWKWKHGD\RILQIXVLRQDQGWKHGD\DIWHULQIXVLRQ
23.1.1.3 Imputation for sensitivity analysis assessing the impact of use of transitional 
medication for eCH
7RUHIOHFWWKHVHWRIVWUDWHJLHVXVHG IRUWKHVHQVLWLYLW\DQDO\VLVGDWDFROOHFWHGRQWKHGD\VDIWHU
XVHRIWUDQVLWLRQDOPHGLFDWLRQ*21EORFNDQGRUDOVWHURLGVZLOOQRWEHXVHGIRUWKLVDQDO\VLV
ZKHQJHQHUDWLQJWKHZHHNO\VFRUHV
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
)RUWKHGDWDUHPDLQLQJDIWHUUHPRYDORIGDWDLQWKH3%2FRQWUROOHG3HULRG IROORZLQJ
WUDQVLWLRQDOPHGLFDWLRQ *21EORFNDQGRUDOVWHURLGVSHULRGVZKHUHWKHH'LDU\LVFRPSOHWHG
RQDWOHDVWRXWRIWKHGD\V ZLOOEHSURUDWHGE\ LPSXWLQJ E\WKHREVHUYHGPHDQQXPEHURI
DWWDFNVLQWKHSHULRGDVIROORZV
7*(Reported number of attacks/Reported eDiary Days)
23.1.1.4 Responder Rates
7KHIROORZLQJUHVSRQGHUUDWHVZLOOEHGHULYHGDQG$UHVSRQGHULVDSDWLHQW
ZKRDFKLHYHVDUHGXFWLRQUHGXFWLRQRUUHGXFWLRQIURP%DVHOLQHLQZHHNO\
QXPEHURIDWWDFNVDWDFHUWDLQZHHNFRPSDUHGWRWKHEDVHOLQHZHHNO\QXPEHURIDWWDFNV7KH
GHULYDWLRQRIWKHVHUHVSRQGHUHQGSRLQWVZLOOEHEDVHGRQWKHZHHNO\QXPEHURIDWWDFNV
UHVXOWLQJIURPWKHLPSXWDWLRQVGHVFULEHGLQVHFWLRQ
)RUUHVSRQVHDFURVVPRUHWKDQRQHZHHNO\SHULRGWKHDYHUDJHRIWKHFKDQJHIURPEDVHOLQHIRU
HDFKZHHNO\SHULRGLVFDOFXODWHGDQGGLYLGHGE\WKHEDVHOLQHYDOXHDQGWKHUHVXOWXVHGWR
GHWHUPLQHWKHUHVSRQVHDFURVVWKHZHHNO\SHULRGV $VDQH[DPSOHWKHUHGXFWLRQIURP
%DVHOLQHLQWKHQXPEHURIZHHNO\DWWDFNV:HHNVLVFDOFXODWHGDVIROORZV
Response = 1, if
(Change from baseline in the number of weekly attacks (Week 1) 
+
Change from baseline in the number of weekly attacks (Week 2))
/(2 x Baseline number of weekly attacks) 
<= -0.5, else Response = 0.
,IRQHRUPRUHZHHNO\VFRUHLVPLVVLQJ IRUDSDWLHQWWKHDYHUDJHRIWKHH[LVWLQJVFRUHVIRUWKDW
SDWLHQW DUHFDOFXODWHGZLWKLQWKHVSHFLILHGLQWHUYDO DQGXVHGIRUFDOFXODWLRQRIUHVSRQVH,IDOO
ZHHNO\VFRUHVDUHPLVVLQJ WKHQWKHUHVSRQVHZLOOEHVHWWRQRQUHVSRQVH
23.1.1.5 Time from first infusion of eptinezumab to resolution of cluster headache bout 
(within the first 4 weeks and 16 weeks) 
7KHHQGSRLQW7LPHIURPILUVWLQIXVLRQRIHSWLQH]XPDEWRUHVROXWLRQRIFOXVWHUKHDGDFKHERXW
ZLWKLQWKHILUVWZHHNVLVRQO\GHILQHGDQGFDOFXODWHGIRUSDWLHQWVUDQGRPL]HGWR
HSWLQH]XPDEDW%DVHOLQH
5HVROXWLRQLVGHILQHGDVWKHGD\DIWHUWKHODVWGD\ZLWKFOXVWHUKHDGDFKHDWWDFNVRIPRGHUDWHRU
VHYHUHSDLQRUZKHUHDERUWLYHPHGLFDWLRQWULSWDQVRU 2ZDVXVHGZKLFKHYHULVWKHODWHVW
ZKHQWKLVLVIROORZHGE\DZHHNSHULRGIUHHRIFOXVWHUKHDGDFKH DWWDFNVRUZLWKFOXVWHU
KHDGDFKHDWWDFNVZLWKRQO\PLOGSDLQQRWUHTXLULQJWKHXVHRIDERUWLYHPHGLFDWLRQZKHUH
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
ERWKZHHNVLQWKHZHHNSHULRGKDGDWOHDVWGD\VRIH'LDU\FRPSOLDQFH6KRXOGWKLVKDSSHQ
PRUHWKDQRQFHLWZLOOEHWKHILUVWLQVWDQFHWKDWFRXQWVDVUHVROXWLRQ7KHZHHNSHULRGIUHH
RIDWWDFNVRUZLWKRQO\PLOGSDLQDUHDOORZHGWRVWDUWRQDQ\GD\ZLWKLQWKHSHULRGDQGQRW
FRQILQHGWR'D\'D\HWF 6LQFHWKHH'LDU\LVRQO\PHDVXUHGXQWLO:HHNUHVROXWLRQFDQ
RQO\KDSSHQEHWZHHQ'D\DQG:HHNVLQFHLWQHHGVWREHIROORZHGE\WZRZHHNVRI
H'LDU\GDWDWKDWIXOILOVWKHFULWHULDPHQWLRQHGDERYH
23.1.2
Patient Global Impression of Change (PGIC)
7KH3*,&LVDVLQJOHSDWLHQWUHSRUWHGLWHPUHIOHFWLQJWKHSDWLHQW¶VLPSUHVVLRQRIFKDQJHLQ
WKHLUGLVHDVHVWDWXVVLQFHWKH%DVHOLQH9LVLW'D\9LVLWWKDWLVLQUHODWLRQWRDFWLYLW\
OLPLWDWLRQVV\PSWRPVHPRWLRQVDQGRYHUDOOTXDOLW\RIOLIH7KHLWHPLVUDWHGRQDSRLQW
VFDOHZKHUHDORZVFRUHLQGLFDWHLPSURYHPHQWIURPYHU\PXFKLPSURYHGWR YHU\PXFK
ZRUVH
23.1.3
Sleep Impact Scale (SIS)
7KH6,6 LVDSDWLHQWUHSRUWHGVFDOHWRDVVHVVTXDOLW\RIOLIHUHVXOWLQJIURPVOHHSGLVWXUEDQFH
7KH6,6TXHVWLRQQDLUHLQFOXGHVLWHPVEHORQJLQJWRGRPDLQVWRDVVHVVVOHHSLPSDFWGDLO\
DFWLYLWLHVLWHPVHPRWLRQDOZHOOEHLQJLWHPVHPRWLRQDOLPSDFWLWHPV
HQHUJ\IDWLJXHLWHPVVRFLDOZHOOEHLQJLWHPVPHQWDOIDWLJXHLWHPVDQGVDWLVIDFWLRQ
ZLWKVOHHSLWHPV(DFKLWHPIRURXWRIWKHGRPDLQVLVUDWHGRQDSRLQWVFDOHUDQJLQJ
IURP³DOZD\V´RU³DOORIWKHWLPH´WR³QHYHU´RU³QRQHRIWKHWLPH´ZKHUHDV
VDWLVIDFWLRQZLWKVOHHSLVUDWHGRQDSRLQWVFDOHUDQJLQJIURPYHU\VDWLVILHGWRYHU\
GLVVDWLVILHG(DFKGRPDLQ\LHOGVDVFRUHUDQJLQJIURP
,WHPVZLWKLQHDFKGRPDLQZHUHVXPPHGDQGWUDQVIRUPHGWRD±VFDOHXVLQJWKHIRUPXOD
>ȈLWHPV± RILWHPVUDQJH@
$KLJKHUVFRUHLQGLFDWHGEHWWHUTXDOLW\RIOLIHUHYHUVHVFRULQJIRUWKHVDWLVIDFWLRQZLWKVOHHS
GRPDLQ
23.1.4
Euroqol 5 Dimension – 5 Levels (EQ-5D-5L)
7KH(4'/ LVDSDWLHQWUHSRUWHGDVVHVVPHQWGHVLJQHGWRPHDVXUHWKHSDWLHQW¶VZHOOEHLQJ
,WFRQVLVWVRIGHVFULSWLYHLWHPVPRELOLW\VHOIFDUHXVXDODFWLYLWLHVSDLQGLVFRPIRUWDQG
GHSUHVVLRQDQ[LHW\DQGDYLVXDODQDORJXHVFDOH9$6RIWKHRYHUDOOKHDOWKVWDWH(DFK
GHVFULSWLYHLWHPLVUDWHGRQDSRLQWLQGH[UDQJLQJIURPQRSUREOHPVWRH[WUHPH
SUREOHPV7KH9$6UDQJHVIURPworst imaginable health stateWRbest imaginable 
health state7KHUHVSRQGHQWVUDWHWKHLURYHUDOOKHDOWKRQWKHGD\RIWKHLQWHUYLHZRQD±
KDVKPDUNHGYHUWLFDOYLVXDODQDORJXHVFDOH
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
23.1.5
Health Care Resource Utilization (HCRU)
&OXVWHUKHDGDFKHVSHFLILFKHDOWKFDUHUHVRXUFHXWLOL]DWLRQLQIRUPDWLRQZLOOEHFROOHFWHGLQ
WHUPVRIRXWSDWLHQWKHDOWKFDUHSURIHVVLRQDOYLVLWVHPHUJHQF\URRPYLVLWVKRVSLWDO
DGPLVVLRQVDVZHOODVGXUDWLRQRIKRVSLWDOVWD\V GXULQJWKHSDVWZHHNV&OLQLFDOVLWH
SHUVRQQHODQGSDWLHQWVZLOOEHLQVWUXFWHGWRFDSWXUHXWLOL]DWLRQWKDWWDNHVSODFHRXWVLGHRIYLVLWV
DVVRFLDWHGZLWKWKHLUSDUWLFLSDWLRQLQWKHFOLQLFDOWULDO
23.1.6
Work Productivity and Activity Impairment: General Health version 2 
(WPAI:GH2.0)
7KH:3$,*+ LVDSDWLHQWVHOIUDWHGVFDOHGHVLJQHGWRSURYLGHDTXDQWLWDWLYHPHDVXUHRI
WKHZRUN SURGXFWLYLW\DQGDFWLYLW\LPSDLUPHQWGXHWRDKHDOWKFRQGLWLRQ7KH:3$,*+
DVVHVVDFWLYLWLHVRYHUWKHSUHFHGLQJGD\VDQGFRQVLVWVRILWHPVLWHPWRDVVHVVZKHWKHU
WKHSDWLHQWKDVDSDLGMRELWHPVDVVHVVWKHQXPEHURIKRXUVZRUNHGWKHQXPEHURIKRXUV
PLVVHGIURPZRUNGXHWRWKHSDWLHQW¶VFRQGLWLRQRUGXHWRRWKHUUHDVRQVDQGYLVXDO
QXPHULFDOVFDOHVDVVHVVKRZPXFKWKHSDWLHQW¶VFRQGLWLRQDIIHFWVWKHLUSURGXFWLYLW\DWZRUN
DQGWKHLUDELOLW\WRFRPSOHWHQRUPDOGDLO\DFWLYLWLHV
7KHGHULYDWLRQRIWKH:3$,*+VXEVFRUHV LVJLYHQLQ 3DQHOZKHUH44UHIHUVWR
TXHVWLRQLQWKHTXHVWLRQQDLUH
Panel 4
Derivation of WPAI:GH2.0 sub-scores
Sub-score
Description
Derivation
$EVHQWHHLVP
3HUFHQWZRUNWLPHPLVVHGGXHWR
KHDOWKSUREOHPV
444
3UHVHQWHHLVP
3HUFHQWLPSDLUPHQWZKLOH
ZRUNLQJGXHWRKHDOWKSUREOHPV
4
:RUNSURGXFWLYLW\ORVV
3HUFHQWRYHUDOOZRUNLPSDLUPHQW
GXHWRKHDOWKSUREOHPV
100 ∗
	
	 
 + 1 −
	
	 
  ∗


$FWLYLW\LPSDLUPHQW
3HUFHQWDFWLYLW\LPSDLUPHQWGXH
WRKHDOWKSUREOHPV
4
,IWKHDQVZHUWR4$UH\RXFXUUHQWO\HPSOR\HGZRUNLQJIRUSD\"LVµ<HV¶EXW4'XULQJ
WKHSDVWVHYHQGD\VKRZPDQ\KRXUVGLG\RXPLVVIURPZRUNEHFDXVHRI\RXUKHDOWK
SUREOHPV"DQG4'XULQJWKHSDVWVHYHQGD\VKRZPDQ\KRXUVGLG\RXDFWXDOO\ZRUN"DUH
ERWKWKHQWKHGHULYHGVFRUHVIRU$EVHQWHHLVPDQG:RUNSURGXFWLYLW\VFRUHZLOOEHVHWWR
PLVVLQJ
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
23.2 Assigning Data to Visits
23.2.1
Rating Scales
Panel 5
Windowing rules for scales
2QO\DVVHVVPHQWVDWZLWKGUDZDOYLVLWVRUXQVFKHGXOHGYLVLWVZLOOEHZLQGRZHG
HCRU
WPAI
PGIC
EQ-5D
SIS
Day
Day, PBO-controlled Period

WR

WR
WR
WR

WR
WR
WR
WR

Day, Delayed Start period
WR
 WR
WR
WR

WR
WR

!
!
!
!

$VZLWKGUDZDOYLVLWVFDQRFFXULQWKH'HOD\HG6WDUW3HULRGWKHZLQGRZLQJLVDOVRDSSOLHGLQ
WKLVSHULRGHYHQWKRXJKVRPHVFDOHVGRQRWKDYHQRPLQDOYLVLWVLQWKHSHULRG
,IWKHUHDUH FRPSHWLQJYLVLWV WKHYDOXHWKDWZLOOEHXVHGLQVXPPDU\WDEOHVE\YLVLWZLOOEHWKH
RQHWKDWSULRULWL]HVYDOXHVIURPZLWKGUDZDO YLVLWVDERYHYDOXHVIURP QRPLQDO DQGWKHQ
XQVFKHGXOHGYLVLWV
,QWKHRUGHULQJRIPXOWLSOHDVVHVVPHQWVSHUYLVLWDVVHVVPHQWVZLOOEHRUGHUHGE\UHFRUGHG
WLPHDQGDVVHVVPHQWVZLWKRXW UHFRUGHGWLPHZLOOFRPHEHIRUH DVVHVVPHQWVZLWKUHFRUGHGWLPH
DQGWKHODVW LQWKHRUGHULQJZLOO EHSLFNHG
)RUVFDOHVDVVHVVHG DIWHU,03LQIXVLRQ EXWVKRXOGKDYHEHHQDVVHVVHG SULRUWR ,03LQIXVLRQ
WKHDVVHVVPHQWZLOOEHDVVLJQHGWRWKHWLPHSRLQWZKHUHLWVKRXOGKDYHEHHQDVVHVVHG 7KDW
LQFOXGHVWKHEDVHOLQHSHULRGDVZHOO
7KHVHHYHQWVZLOOEHGLVFXVVHG DQGGHFLVLRQVGRFXPHQWHGLQFODVVLILFDWLRQPHHWLQJ
)RUH'LDU\GDWDWKHSHULRGVZLOOEHGHILQHGE\WKHDVVHVVPHQWVDFFRUGLQJWKHQXPEHURI
SODQQHGGD\VIURP ILUVW ,03LQIXVLRQ
23.2.2
eDiary
$OOH'LDU\DVVHVVPHQWVXVHGLQHQGSRLQWVDQDO\VLQJDVVHVVPHQWV SHUZHHNDUHZLQGRZHG
XVLQJ WKHSODQQHGGD\VHWF
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
23.2.3
Safety Variables
Panel 6
Windowing rules for Lab and ECG assessments
Lab
ECG
Day
Day, PBO-controlled Period



WR
WR

Day, Active treatment period
WR
WR

!
!

Panel 7
Windowing rules for VS/body assessments
VS/body
Day
Day, PBO-controlled Period
1$
6FUHHQLQJ
1$
SUHGRVH
SRVWGRVHWR'D\
SRVWGRVH
!DQGQG,03LQIXVLRQ
 SUHGRVH
Day, Delayed Start Period
! QG,03LQIXVLRQ DQG 
SRVWGRVH
!DQG 

!

,IWKHUHDUH FRPSHWLQJYLVLWV WKHYDOXHWKDWZLOOEHXVHGLQVXPPDU\WDEOHVE\YLVLWZLOOEHWKH
RQHWKDWSULRULWL]HVYDOXHVIURPQRPLQDO YLVLWVDERYHYDOXHVIURP ZLWKGUDZDORU XQVFKHGXOHG
YLVLWV WKDWLVFORVHVWWRWKHQRPLQDOYLVLW
,QWKHRUGHULQJRIPXOWLSOHDVVHVVPHQWVSHUYLVLWDVVHVVPHQWVZLOOEHRUGHUHGE\UHFRUGHG
WLPHDQGDVVHVVPHQWVZLWKRXW UHFRUGHGWLPHZLOOFRPHEHIRUH DVVHVVPHQWVZLWKUHFRUGHGWLPH
DQGWKHODVW LQWKHRUGHULQJZLOO EHSLFNHG
9LWDO6LJQV SUHGRVHDWEDVHOLQHZLOOEHDVVLJQHGWKHEDVHOLQHSHULRG
,QJHQHUDOODE96DQG(&*ZLOOEHDVVLJQHGSHULRGVDFFRUGLQJWRWKH,03LQIXVLRQV
23.3 Handling Missing or Incomplete Dates/Times
23.3.1
Withdrawal Date
0LVVLQJZLWKGUDZDOGDWHVZLOOQRWEHLPSXWHGDQGWLPHWRZLWKGUDZDOIURPVWXG\ ZLOOQRWEH
FDOFXODWHGIRUPLVVLQJZLWKGUDZDOGDWHV
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
23.3.2
IMP Start and Stop time points
1RLPSXWDWLRQVZLOOEHGRQHLI,03VWDUWDQGRU HQGWLPHSRLQWLVPLVVLQJ
23.3.3
Medical Disorder Start and Stop Dates
,QFRPSOHWHGDWHVZLOOQRWEHLPSXWHG&ODVVLILFDWLRQRIHYHQWVLQWRconcurrent medical 
disorders RUpast disorders ZLOOEHEDVHGRQWKHUHSRUWHGRQJRLQJVWDWXV
23.3.4
Medication Start and Stop Dates
,PSXWDWLRQRILQFRPSOHWHRUSDUWLDOO\PLVVLQJGDWHVZLOOEHSHUIRUPHGLQRUGHUWRGRFXPHQW
WKHDVVLJQHGFDWHJRULHVVSHFLILHGLQFKDSWHU 
7KHDOJRULWKPIRULPSXWLQJWKHVWDUWGDWHVZLOOIROORZWKHRQHXVHGIRULPSXWLQJDGYHUVHHYHQW
VWDUWGDWHVVHHVHFWLRQ  ,ISDUWO\PLVVLQJVWDUWGDWHVRFFXUWKH\ZLOORQO\EHLPSXWHG
IRUVXPPDUL]LQJWKHXVHRIFRQFRPLWDQWPHGLFDWLRQQRWIRUWKHVHQVLWLYLW\DQDO\VLVIRUWKH
SULPDU\HQGSRLQW
)RULPSXWLQJVWRSGDWHVWKHIROORZLQJZLOODSSO\ZKHUH8.DQG8.1LQGLFDWHXQNQRZQRU
PLVVLQJGD\DQGPRQWKUHVSHFWLYHO\

8.000<<<<0HGLFDWLRQ HQGGDWHLV LPSXWHGZLWKWKHODVWGD\RIWKHPRQWK

8.8.1<<<<0HGLFDWLRQ HQGGDWHLV LPSXWHGZLWK'(&<<<<
0HGLFDWLRQVPDUNHGDVRQJRLQJDUHFRQVLGHUHGFRQFRPLWDQWPHGLFDWLRQVLQRQHRUERWKRIWKH
SHULRGV3ODFHERFRQWUROOHG3HULRGDQG'HOD\HG6WDUW3HULRGGHSHQGLQJRQWKHSRVVLEO\
LPSXWHGVWDUWGDWHLHLIWKHVWDUW GDWHLVDWRUDIWHUWKHGDWHRI9,03LQIXVLRQWKH
PHGLFDWLRQLVRQO\FRQVLGHUHGRQJRLQJLQWKH'HOD\HG6WDUW3HULRG ,IQRLQIRUPDWLRQDWDOOLV
SURYLGHGWKHQPHGLFDWLRQLVFRQVLGHUHGRQJRLQJLQERWKSHULRGV
23.3.5
Adverse Event Start and Stop Dates
,PSXWDWLRQRISDUWLDOO\RUFRPSOHWHO\PLVVLQJGDWHVZLOOEHLQFOXGHGLQGDWDLQRUGHUWR
GRFXPHQWWKHFODVVLILFDWLRQRIWKHWUHDWPHQWHPHUJHQWVWDWXVDQGDVVLJQPHQWRIWKHDGYHUVH
HYHQWWRDSHULRG)RUDQDGYHUVHHYHQWZLWKDQLPSXWHGVWDUWGDWHWKHFODVVLILFDWLRQRI
WUHDWPHQWHPHUJHQWZLOOGHSHQGRQO\RQZKHWKHUWKHLPSXWHGGDWHLVWKHVDPHDVWKHGDWHVRI
LQIXVLRQDQGQRWWKHWLPHSRLQWRIWKHLQIXVLRQVLQFHVWDUWWLPHVIRUDGYHUVHHYHQWVZLOOQRWEH
LPSXWHG1RGXUDWLRQZLOOEHFDOFXODWHGIRUDGYHUVHHYHQWV ZLWKLQFRPSOHWHVWDUWRUVWRS
GDWHV
,PSXWDWLRQZLOOIROORZWKHDOJRULWKPEHORZ,IDQLPSXWHGVWDUWGDWHDIWHUWKLVSURFHGXUHLV
DIWHUWKHHQGGDWHWKHVWDUWGDWHZLOOEHVHWWRWKHHQGGDWH
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Start Dates
Patients with no IMP infusion
)RUSDWLHQWVZKRKDYHQRWEHHQWUHDWHGWKHLPSXWDWLRQRI$(VWDUWGDWHZLOOEHSHUIRUPHGDV
IROORZVZKHUH8.DQG8.1LQGLFDWHXQNQRZQRUPLVVLQJGD\DQGPRQWKUHVSHFWLYHO\

8.000<<<< 7KHVWDUWGDWHZLOOEHLPSXWHGZLWKHLWKHUWKHVW RIWKHPRQWKRUGDWH
RI9LVLW'DWHRI9LVLWZLOOEHXVHGLIWKDWLVWKHODWHURIWKHWZRDQGLILWLVZLWKLQWKH
VSHFLILHGPRQWKDQG\HDU

8.8.1<<<<7KHVWDUWGDWHZLOOEHLPSXWHGZLWKHLWKHU-$1RUGDWHRI9LVLW
'DWHRI9LVLWZLOOEHXVHGLILWLVZLWKLQWKHVSHFLILHG\HDU
,IWKH$(VWDUWGDWHLVFRPSOHWHO\PLVVLQJLWZLOOEHVHWHTXDOWRWKHGDWHRI9LVLW
Patients that have been treated
)RUSDWLHQWVZKRKDYHEHHQWUHDWHGWKHLPSXWDWLRQRI$(VWDUWGDWHVZLOOEHSHUIRUPHGDV
IROORZV

8.000<<<<
o ,IWKH\HDUDQGPRQWKDUHHTXDOWRWKH\HDUDQGPRQWKRIWUHDWPHQWVWDUWGDWHWKH
DGYHUVHHYHQWVWDUWGDWHLVLPSXWHGZLWKWKHGDWHRIILUVWGRVHRI,03
o ,IWKH\HDULVHTXDOWRWKH\HDURIWUHDWPHQWVWDUWGDWH,IWKHPRQWKLVSULRUWRWKH
WUHDWPHQWVWDUWGDWHWKHDGYHUVHHYHQWVWDUWGDWHLVLPSXWHGZLWKWKHODVWGD\RIWKH
PRQWK,IWKHPRQWKLVHTXDOWRWKHPRQWKRIWKHWUHDWPHQWVWDUWGDWHVHHDERYH,IWKH
PRQWKLVDIWHUWKHPRQWKRIWKHWUHDWPHQWVWDUWGDWHWKHDGYHUVHHYHQWVWDUWGDWHLV
LPSXWHGZLWKWKHILUVWGD\RIWKHPRQWK
o ,IWKH\HDULVSULRUWRWUHDWPHQWVWDUWGDWHWKHDGYHUVHHYHQWVWDUWGDWHLVLPSXWHGZLWKWKH
ODVWGD\RIWKHPRQWK
o ,IWKH\HDULVDIWHUWKH\HDURIWUHDWPHQWVWDUWGDWH WKHDGYHUVHHYHQWVWDUWGDWHLVLPSXWHG
ZLWKWKHILUVWGD\RI WKH PRQWK

8.8.1<<<<
o ,IWKH\HDULVHTXDOWRWKH\HDURIWUHDWPHQWVWDUWGDWHWKHDGYHUVHHYHQWVWDUWGDWHLV
LPSXWHGZLWKWUHDWPHQWVWDUWGDWH
o ,IWKH\HDULVSULRUWRWKH\HDURIWUHDWPHQWVWDUWGDWHWKHDGYHUVHHYHQWVWDUWGDWHLV
LPSXWHGZLWK'(&<<<<
o ,IWKH\HDULVDIWHUWKH\HDURIWUHDWPHQWVWDUWGDWHWKHDGYHUVHHYHQWVWDUWGDWHLVLPSXWHG
ZLWK-$1<<<<
,IWKH$(VWDUWGDWHLVFRPSOHWHO\PLVVLQJLWZLOOEHVHWHTXDOWRWUHDWPHQWVWDUWGDWH
End Dates
0LVVLQJ$(HQGGDWHVZLOOQRWEHLPSXWHG
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Incomplete Intensity Change Dates
,IWKHGD\LVPLVVLQJLQDGDWHRILQWHQVLW\FKDQJHIRUDQDGYHUVHHYHQWWKHGDWHZLOOEH
LPSXWHGXVLQJWKHVDPHDOJRULWKPDVGHVFULEHGDERYH IRULQFRPSOHWHDGYHUVHHYHQWVWDUWGDWHV
,IWKLVUHVXOWVLQDQLPSXWHGVWDUWGDWHWKDWLVDIWHUWKHHQGGDWHRIWKHRULJLQDOHYHQWRUDIWHUDQ
LQWHQVLW\FKDQJHWKDWFRPHVDIWHUWKHLQWHQVLW\FKDQJHLQTXHVWLRQWKHVWDUWGDWHZLOOEH
LPSXWHGZLWKWKHHQG GDWHRIWKHRULJLQDOHYHQWRUWKHGDWHRIWKHODWHULQWHQVLW\RUFKDQJH
23.4 Treatment-emergent AEs
Event
Treatment-emergent (Yes/No)
$(VWDUWVDWRUDIWHUILUVWGRVHRI,03
<HV
&KDQJHLQLQWHQVLW\
-
,ISULRUWRILUVW,03 !1R
-
,IDWRUDIWHUILUVW,03AND LQWHQVLW\LQFUHDVH !
<HV
-
,IDWRUDIWHUILUVW,03AND LQWHQVLW\GHFUHDVH !
1R
$(EHFRPHV6$(
-
,ISULRUWRILUVW,03 !1R
-
,IDWRUDIWHUILUVW,03 !<HV
(YHQWVWKDWKDSSHQVLPXOWDQHRXVO\
6$(DQGFKDQJHLQLQWHQVLW\
-
,ISULRUWRILUVW,03 !1R
-
,IDWRUDIWHUILUVW,03 !<HVGXHWR6$(
UHJDUGOHVVRIWKHGLUHFWLRQRIWKHLQWHQVLW\FKDQJH
23.5 Data with Multiple Records
23.5.1
Dose Changes in Medication Events
'RVHFKDQJHVLQPHGLFDWLRQVDUHUHFRUGHGRQPXOWLSOHURZVLQWKHGDWDVHWZLWKGLIIHUHQWVWDUW
DQGVWRSGDWHV:KHQFODVVLI\LQJPHGLFDWLRQVLQWRFDWHJRULHV VHHFKDSWHUHDFKGRVHLV
FRQVLGHUHGDVHSDUDWHPHGLFDWLRQDQGWKHVDPHPHGLFDWLRQ FDQEHDVVLJQHGWRVHYHUDO
FDWHJRULHV IRUWKHVDPHSDUWLFLSDQW:LWKLQDFDWHJRU\PXOWLSOHHQWULHVFRQWULEXWHDVDVLQJOH
FRXQW
23.5.2
Changes in Intensity or Seriousness of Adverse Events
$QDGYHUVHHYHQWWKDWFKDQJHVLQLQWHQVLW\ LQDSHULRG ZLOOFRQWULEXWHWRWKHFRXQWRIHYHQWVDV
DVLQJOHHYHQW
,QVXPPDULHVRIDGYHUVHHYHQWVSUHVHQWHGE\LQWHQVLW\WKHPD[LPXPLQWHQVLW\RIWKHDGYHUVH
HYHQWZLOOEHXVHG7KHPD[LPXPLQWHQVLW\LVVHDUFKHGIRULQHYHQWVZLWKFKDQJHVDVZHOODV
RYHUUHSHDWHGHYHQWVEDVHGRQWKHSUHIHUUHGWHUP$GYHUVHHYHQWVIRUZKLFKLQIRUPDWLRQRQ
LQWHQVLW\LVPLVVLQJZLOOEHFODVVLILHGDVsevere
$GYHUVHHYHQWVZLWKDQXSGDWH LQVHULRXVQHVVZLOOEHLQFOXGHGLQ$'D0ZLWKDQHZ URZ)RU
VXFKDQHYHQWWKHVWDUWGDWHRIWKHVHULRXVDGYHUVHHYHQWZLOOEHVHWWRWKHVWDUWGDWHRIWKH
FKDQJHRIVHULRXVQHVV7KLVPHDQVWKDWDQDGYHUVHHYHQWZLWKDVWDUWGDWHSULRUWRILUVWLQIXVLRQ
RI,03LHQRWFODVVLILHGDVWUHDWPHQWHPHUJHQWWKDWLVUHJLVWHUHGDVVHULRXVDIWHUILUVW,03
LQIXVLRQZLOOEHFODVVLILHGDVWUHDWPHQWHPHUJHQW
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
$GYHUVHHYHQWVIRUZKLFKLQIRUPDWLRQRQVHULRXVQHVVLVPLVVLQJZLOOEHFODVVLILHGDVserious
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
References

5DWLWFK%/LSNRYLFK,2¶.HOO\0&RPELQLQJDQDO\VLVUHVXOWVIURPPXOWLSO\LPSXWHGFDWHJRULFDO
'DWD3KDUPD68*3DSHU63

8QLWHG6WDWHV)RRGDQG'UXJ$GPLQLVWUDWLRQ86)'$*XLGDQFHIRU,QGXVWU\'UXJLQGXFHG
OLYHULQMXU\SUHPDUNHWLQJFOLQLFDOHYDOXDWLRQ-XO\

*RDGVE\3-'RGLFN':/HRQH0%DUGRV-12DNHV700LOOHQ%$HWDO7ULDORI
*DOFDQH]XPDELQ3UHYHQWLRQRI(SLVRGLF&OXVWHU+HDGDFKH1(QJO-0HG-XO


&UDZIRUG%%XUJHVV6%XUHOO$HWDO'HYHORSPHQWDQGYDOLGDWLRQRIWKHVOHHSLPSDFWVFDOHIRU
LQVRPQLD9DOXHLQ+HDOWK$

+HUGPDQ0*XGH[&/OR\G$-DQVVHQ0.LQG33DUNLQ'HWDO'HYHORSPHQWDQG
SUHOLPLQDU\WHVWLQJRIWKHQHZILYHOHYHOYHUVLRQRI(4'(4'/4XDOLW\RI/LIH
5HVHDUFK±

5HLOO\0&=EUR]HN$6'XNHV(07KHYDOLGLW\DQGUHSURGXFLELOLW\RIDZRUNSURGXFWLYLW\DQG
DFWLYLW\LPSDLUPHQWLQVWUXPHQW3KDUPDFRHFRQRPLFV±

5HLOO\$VVRFLDWHV:3$,6FRULQJ>,QWHUQHW@UHLOO\DVVRFLDWHVQHW:3$,B6FRULQJKWPO
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Appendix I
Statistical Analysis Plan
Authentication and Authorization
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Statistical Analysis Plan
Authentication and Authorization
6WXG\WLWOH
,QWHUYHQWLRQDOUDQGRPL]HGGRXEOHEOLQGSDUDOOHOJURXSSODFHERFRQWUROOHG
GHOD\HGVWDUWVWXG\WRHYDOXDWHWKHHIILFDF\DQGVDIHW\RIHSWLQH]XPDELQSDWLHQWV
ZLWKHSLVRGLF&OXVWHU+HDGDFKH
6WXG\ 1R
$
6$3GDWH
2FWREHU
7KLVGRFXPHQWKDVEHHQVLJQHGHOHFWURQLFDOO\7KHVLJQDWRULHVDUHOLVWHGEHORZ
Authentication
Authorization
33'
33'
33'
33'
33'
33'
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Appendix II
SAS® Code
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
SAS® Code
PRIMARY ANALYSIS
Key elements of the pMI analysis:
* Step1: Create a number of data sets, where MCMC is used to make 
all data sets monotone missing;
proc sort data=adam.adeffch (where=(RANDFL='Y' and 
paramcd='ATTACKW')) out=adeffch;
by usubjid trt01p base AVISITN;
run;
proc transpose data = adeffch out = adeffch_mi (drop = _NAME_ 
_LABEL_) prefix = AVISITN_;
    by USUBJID TRT01P BASE COUNTRY;
    var CHG;
    id AVISITN;
run;
proc sort data=adeffch_mi;
by trt01p;
run;
proc mi data = adeffch_mi out = Org_im nimpute = 200 seed = 210876;
by trt01p;
var base avisitn_1 avisitn_2 avisitn_3 avisitn_4;
mcmc chain = multiple
impute = monotone;
run;
* Step 2: Impute missing values within specified class variables;
* Use placebo mean imputation by using the placebo variables to im-
pute from;
proc sort data = Org_im;
by _IMPUTATION_;
run;
proc mi data = Org_im seed = 67653179 nimpute = 1 out = Org_im2;
by _IMPUTATION_;
class trt01p;
monotone regression;
mnar model(avisitn_1 avisitn_2 avisitn_3 avisitn_4/ modelobs = 
(trt01p = 'PBO')); 
var base avisitn_1 avisitn_2 avisitn_3 avisitn_4;
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
run;
* Transform back to vertical structure;
proc sort data = Org_im2;
by _IMPUTATION_ usubjid;
run;
proc transpose data = Org_im2 out = MI (rename=(COL1=CHG 
_NAME_=AVISIT));
by _IMPUTATION_ USUBJID BASE TRT01P COUNTRY;
var avisitn_1 avisitn_2 avisitn_3 avisitn_4;
run;
proc sort data=MI out=MI_final;
by _IMPUTATION_;
run;
proc mixed noclprint data= MI_final ic method=reml;
by _IMPUTATION_;
class usubjid country (ref=’xxx’) trt01p avisit;
model chg = base*avisit country trt01p*avisit /s ddfm=kr;
repeated avisit /subject=usubjid type=UN;
lsmeans trt01p*avisit / diff cl;
estimate 'EPTI 400 mg vs PBO Week 1-2' trt01p*avisit 1 1 0 0
-1 -1 0 0/ divisor=2;
ods output estimates=est_chg_MI;
run;
proc mianalyze data = est_chg_MI;
modeleffects Estimate;
stderr StdErr;
ods output ParameterEstimates = param_est;
run;
)RUSDWLHQWVZLWKGD\VZLWKREVHUYDWLRQVGXULQJWKH%DVHOLQH3HULRG
*Create 200 random baselines based on baseline mean and SD from all 
patients;
data random_baselines;
seed =38264387;
do obs = 1 to 200;
baseline_random = rand ('normal',mean,SD);
output;
end;
run;
*Create i=1 to 200 random seeds for the monotone procedure;
data random_seeds;
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
   call streaminit(884);
   do i = 1 to 200;
   random_seed = rand("integer", 1000000, 2000000);
   output;
   end;
run;
* create i=1 to 200 data sets (one for each random seed from above) 
using the baseline_random simulated above: one baseline per data 
set;
For i=1 to 200;
proc mi data = xxx_i out = yyy nimpute = 1 seed = i;
by trt01p;
var baseline_random avisitn_1 avisitn_2 avisitn_3 avisitn_4;
mcmc chain = multiple
impute = monotone;
run;
* Now there are simulated 200 data sets, and the procedure of imput-
ing missing values and estimate the treatment effect is the same as 
for the primary analysis shown in the beginning of this appendix;
KEY SECONDARY ANALYSIS
Response
proc logistic data = xyz;
by week;
class treatment(ref = "PBO") region / param = GLM;
model RESPONSE(event = "1") = base region treatment /
clodds = PL alpha = 0.05;
run;
Time from infusion to resolution
proc phreg data = xyz;
class treatment duration;
model TIME * STATUS(0) = base treatment duration/ ties = EFRON;
hazardratio treatment / cl = pl;
run;
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Appendix III
PCS Criteria
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
PCS Criteria
Table 1
PCS Criteria for Clinical Safety Laboratory Tests
Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
Haematology / Coagulation
%KDHPRJORELQ
+*%
J/
ZRPHQ
ZRPHQ
PHQ
PHQ
%HU\WKURF\WHVUHGFHOOFRXQW
5%&
[(/
ZRPHQ
ZRPHQ
PHQ
PHQ
%KDHPDWRFULWSDFNHGFHOO
YROXPH
+&7
99
ZRPHQ
ZRPHQ
PHQ
PHQ
%0&9PHDQFHOOYROXPH
0&9
I/
[//1
[8/1
%WRWDOOHXFRF\WHZKLWHFHOO
FRXQW
:%&
[(/


%QHXWURSKLOVOHXFRF\WHV
1(87/(



%HRVLQRSKLOVOHXFRF\WHV
(26/(


%EDVRSKLOVOHXFRF\WHV
%$62/(


%O\PSKRF\WHVOHXFRF\WHV
/<0/(



%PRQRF\WHVOHXFRF\WHV
0212/(


%WKURPERF\WHVSODWHOHWFRXQW
3/$7
[(/


3,15SURWKURPELQUDWLR
,15
5DWLR

%SURWKURPELQWLPH
37
6HF

Liver
6DVSDUWDWHDPLQRWUDQVIHUDVH
$67
,/
î8/1
6DODQLQHDPLQRWUDQVIHUDVH
$/7
,/
î8/1
6ELOLUXELQ
%,/,
ȝPRO/

6ELOLUXELQGLUHFW
%,/',5
ȝPRO/

6ELOLUXELQLQGLUHFW
%,/,1'
ȝPRO/

6DONDOLQHSKRVSKDWDVH
$/3
,/
î8/1
6JDPPDJOXWDP\OWUDQVIHUDVH
**7
,/

6DOSKDJOXWDWKLRQH6WUDQVIHUDVH
DOSKD*67
*67$/
ȝJ/

Kidney
6FUHDWLQLQH
&5($7
ȝPRO/
[8/1
%XUHDQLWURJHQ%81
%81
PPRO/

6XULFDFLGXUDWH
85$7(
ȝPRO/
ZRPHQ
PHQ
Electrolytes
6VRGLXPQDWULXP
62',80
PPRO/


6SRWDVVLXPNDOLXP
.
PPRO/


Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
6FDOFLXP
&$
PPRO/


6FKORULGH
&/
PPRO/


6PDJQHVLXP
0*
PPRO/


6SKRVSKDWHSKRVSKRUXV
LQRUJDQLF
3+26
PPRO/


6ELFDUERQDWH
%,&$5%
PPRO/


Endocrine / Metabolic
%JOXFRVHQRQIDVWLQJXQNQRZQ
*/8&
PPRO/


%JOXFRVHIDVWLQJ
*/8&
PPRO/


6JOXFRVHQRQIDVWLQJXQNQRZQ
*/8&
PPRO/


6JOXFRVHIDVWLQJ
*/8&
PPRO/


%JO\FRV\ODWHGKDHPRJORELQ
IDVWLQJ
+%$&
+EIUDFW

6SURODFWLQ
352/&71
P,8/

6WK\URWURSLQ76+
76+
P,8/


6SURWHLQWRWDO
3527
J/


6DOEXPLQ
$/%
J/

Lipids
6FKROHVWHUROWRWDOQRQ
IDVWLQJXQNQRZQ
&+2/
PPRO/

6FKROHVWHUROWRWDOIDVWLQJ
&+2/
PPRO/

6WULJO\FHULGHVQRQ
IDVWLQJXQNQRZQ
75,*
PPRO/

6WULJO\FHULGHVIDVWLQJ
75,*
PPRO/

6/'/FKROHVWHUROQRQ
IDVWLQJXQNQRZQ
/'/
PPRO/

6/'/FKROHVWHUROIDVWLQJ
/'/
PPRO/

6+'/FKROHVWHUROQRQ
IDVWLQJXQNQRZQ
+'/
PPRO/

6+'/FKROHVWHUROIDVWLQJ
+'/
PPRO/

Cardiac/Skeletal/Muscle
6FUHDWLQHNLQDVHWRWDO
&.
,/
ZRPHQ
PHQ
6FUHDWLQHNLQDVH0%LVRHQ]\PH
&.0%
ȝJ/
RU
&.0%&.

RIWRWDO
&.
6ODFWDWHGHK\GURJHQDVHWRWDO
/'+
,8/

6WURSRQLQ,
752321,
ȝJ/

6WURSRQLQ7
7523217
ȝJ/

Infection
6&UHDFWLYHSURWHLQ
&53
PJ/

6JOREXOLQWRWDO
*/2%8/
J/


Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Laboratory Test
CDISC Term
Unit
PCS Low
PCS High
Urine
8ULQDU\S+
3+


6 VHUXP% ZKROHEORRG8 XULQH
Table 2
PCS Criteria for Vital Signs, Weight/BMI, and Waist Circumference
Variable
CDISC Term
Unit
PCS Low
PCS High
:DLVWFLUFXPIHUHQFH
:67&,5
&P
GHFUHDVH
LQFUHDVH
:HLJKW
:(,*+7
.J
GHFUHDVH
LQFUHDVH
%RG\0DVV,QGH[
%0,
NJP
GHFUHDVH
LQFUHDVH
3XOVHUDWH
VXSLQHVLWWLQJXQNQRZQ
38/6(
EHDWVPLQ
DQG
GHFUHDVH
DQG
LQFUHDVH
'LDVWROLFEORRGSUHVVXUH
VXSLQHVLWWLQJXQNQRZQ
',$%3
PP+J
DQG
GHFUHDVH
DQG
LQFUHDVH
6\VWROLFEORRGSUHVVXUH
VXSLQHVLWWLQJXQNQRZQ
6<6%3
PP+J
DQG
GHFUHDVH
DQG
LQFUHDVH
2UWKRVWDWLFV\VWROLFEORRG
SUHVVXUH
2%3
PP+J

2UWKRVWDWLFSXOVHUDWH
235
EHDWVPLQ

7HPSHUDWXUH
7(03
&
GHFUHDVH
DQG
LQFUHDVH
,QFUHDVHGHFUHDVHLVUHODWLYHWRWKHEDVHOLQHYDOXH
Table 3
PCS Criteria for ECG Parameters
ECG Parameter
CDISC Term
Unit
PCS Low
PCS High
Absolute Time Interval
35LQWHUYDO
350($1
0VHF

456LQWHUYDO
456'85
0VHF

47LQWHUYDO
470($1
0VHF

Derived Time Interval
+HDUWUDWH
+50($1
EHDWVPLQ
DQG
GHFUHDVH
DQG
LQFUHDVH
47F%LQWHUYDO
47&%
0VHF

!RU
LQFUHDVH!
47F)LQWHUYDO
47&)
0VHF

!RU
LQFUHDVH!
,QFUHDVHGHFUHDVHLVUHODWLYHWRWKHEDVHOLQHYDOXH
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Appendix IV
Study flow chart
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Study flow chart
Table 4
Study Procedures and Assessments
Visit/Period Name
Screening
Placebo-controlled 
Period
Post-
Treatment 
Observational 
Period 
Screening Period 
1
Screening Period 
2
Baseline Visit 
Primary Outcome 
Visit 
Active Treatment 
Period
Completion Visit
SFU Visit c
Withdrawal Visitd
Visit Number
1a, gg
2a
3a
4b
5b
6a
7b
8b
9a
10a
WDa
Day/
End of Week

WR
/
-53 to
-1
WR

/
0


/
2
/
4
/
8

12
/
16

/24
Visit Windowe (days relative to 
nominal visit)
/1
1
1
1
/5
/5
/5
/5
Screening and Baseline Procedures and Assessments
6LJQHGLQIRUPHGFRQVHQWV
I
J
'HPRJUDSKLFVDJHVH[UDFH

'LDJQRVLV


'LVHDVHVSHFLILFKLVWRU\K

5HOHYDQWKLVWRU\VRFLDO
PHGLFDOSV\FKLDWULF
QHXURORJLFDO


3UHYLRXVFOXVWHUKHDGDFKH
DERUWLYHDQGSUHYHQWLYHWKHUDS\
XVHK


5HFHQWPHGLFDWLRQSDVW
PRQWKVSULRUWRWKH6FUHHQLQJ
9LVLW6FUHHQLQJ9LVLW


6XEVWDQFH8VHHJVPRNLQJ	
DOFRKRO


+HLJKW

)DPLO\KLVWRU\RIFOXVWHU
KHDGDFKH

8ULQHGUXJVFUHHQ

,QFOXVLRQH[FOXVLRQFULWHULDL



Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Visit/Period Name
Screening
Placebo-controlled 
Period
Post-
Treatment 
Observational 
Period 
Screening Period 
1
Screening Period 
2
Baseline Visit 
Primary Outcome 
Visit 
Active Treatment 
Period
Completion Visit
SFU Visit c
Withdrawal Visitd
Visit Number
1a, gg
2a
3a
4b
5b
6a
7b
8b
9a
10a
WDa
Day/
End of Week

WR
/
-53 to
-1
WR

/
0


/
2
/
4
/
8

12
/
16

/24
Visit Windowe (days relative to 
nominal visit)
/1
1
1
1
/5
/5
/5
/5
6LJQVDQGV\PSWRPVSUHVHQWDW
6FUHHQLQJ9LVLWDQG%DVHOLQH
9LVLWEHIRUH,03
DGPLQLVWUDWLRQ UHFRUGHGRQDQ
Adverse Event Formhh


5DQGRPL]DWLRQ

Efficacy Assessments (ePROs) j,k
H'LDU\GDLO\UHFRUGLQJO

P


P



H'LDU\FRPSOLDQFHFKHFNQ








3*,&


P



6,6
P

 P

Pharmacoeconomic Assessments (ePROs)
(4'/
 P

P



+&58 M
 P
P
:3$,*+ M
 P
P
Pharmacokinetic Assessments
%ORRGVDPSOLQJIRU,03
TXDQWLILFDWLRQ
R
R



Pharmacodynamic Assessments
%ORRGVDPSOLQJIRUH[SORUDWRU\
ELRPDUNHUV
R
R



Safety Assessments
$GYHUVHHYHQWV
KK
STU


STU





%ORRGDQGXULQHVDPSOLQJIRU
FOLQLFDOVDIHW\ODERUDWRU\WHVWV

T
T



Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Visit/Period Name
Screening
Placebo-controlled 
Period
Post-
Treatment 
Observational 
Period 
Screening Period 
1
Screening Period 
2
Baseline Visit 
Primary Outcome 
Visit 
Active Treatment 
Period
Completion Visit
SFU Visit c
Withdrawal Visitd
Visit Number
1a, gg
2a
3a
4b
5b
6a
7b
8b
9a
10a
WDa
Day/
End of Week

WR
/
-53 to
-1
WR

/
0


/
2
/
4
/
8

12
/
16

/24
Visit Windowe (days relative to 
nominal visit)
/1
1
1
1
/5
/5
/5
/5
%ORRGVDPSOLQJIRU$'$
LQFOXGLQJ1$EV
T



9LWDOVLJQVLQFOXGLQJERG\
WHPSHUDWXUHZHLJKW
V

TU
TU



(&*

T
T



([DPLQDWLRQVSK\VLFDO
QHXURORJLFDOW






&6656X

T
T




Biobankingv
%ORRGVDPSOLQJIRUJHQH
H[SUHVVLRQSURILOLQJ51$Z




%ORRGVDPSOLQJIRUIXWXUH
H[SORUDWRU\ELRPDUNHUVZ
R
R

%ORRGVDPSOLQJIRU
PHWDERORPLFVSURWHRPLFV
SODVPDZ




%ORRGVDPSOLQJIRU
SKDUPDFRJHQHWLFV'1$
RSWLRQDO[

%ORRGVDPSOLQJIRUSRVVLEOH
IXWXUH$'$DVVHVVPHQWZ\
]



Other Study Procedures and Assessments
,03DGPLQLVWHUHG,9LQIXVLRQDD
EE
EE
,03DFFRXQWDELOLW\FF


&RQFRPLWDQWPHGLFDWLRQ
SUHVFULSWLRQDQGQRQ
SUHVFULSWLRQ

T


T





Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Visit/Period Name
Screening
Placebo-controlled 
Period
Post-
Treatment 
Observational 
Period 
Screening Period 
1
Screening Period 
2
Baseline Visit 
Primary Outcome 
Visit 
Active Treatment 
Period
Completion Visit
SFU Visit c
Withdrawal Visitd
Visit Number
1a, gg
2a
3a
4b
5b
6a
7b
8b
9a
10a
WDa
Day/
End of Week

WR
/
-53 to
-1
WR

/
0


/
2
/
4
/
8

12
/
16

/24
Visit Windowe (days relative to 
nominal visit)
/1
1
1
1
/5
/5
/5
/5
H'LDU\WUDLQLQJ

H352WUDLQLQJ

H'LDU\FORVHRXWGG


3UHJQDQF\WHVWHH


T
T



$'$ DQWLGUXJDQWLERG\%/ EDVHOLQH&6656 &ROXPELD6XLFLGH6HYHULW\5DWLQJ6FDOH(4'/ 
(XUR4RO 'LPHQVLRQ/HYHO+&58 +HDOWK&DUH5HVRXUFHV8WLOL]DWLRQ,03 LQYHVWLJDWLRQDOPHGLFLQDO
SURGXFW,9 LQWUDYHQRXV3*,& 3DWLHQW*OREDO,PSUHVVLRQRI&KDQJHH352 HOHFWURQLFSDWLHQWUHSRUWHG
RXWFRPH6$( VHULRXVDGYHUVHHYHQW6)8 6DIHW\)ROORZXS6,6 6OHHS,PSDFW6FDOH:' :LWKGUDZDO
:3$,*+ :RUN3URGXFWLYLW\$FWLYLW\4XHVWLRQQDLUH*HQHUDO+HDOWKVHFRQGYHUVLRQ
D
7KLVYLVLWVKRXOGEHDVLWHYLVLW7KH6FUHHQLQJ9LVLWDVVHVVPHQWVPD\EHH[WHQGHGRYHUVHYHUDOGD\VLI
QHHGHG7KH GDWHRIWKHILUVWDVVHVVPHQWH[FHSW,&)VKRXOGEHHQWHUHGLQWKH,57V\VWHPDVWKH9LVLW'DWH
E
)RUSKRQHYLVLWVWKHSDWLHQWZLOOEHFRQWDFWHGIRUH'LDU\FRPSOLDQFHFKHFNWRHQVXUHWKDWWKHVHOHFWHG
DVVHVVPHQWVKDYHEHHQFRPSOHWHGDQGIRUFROOHFWLRQRIUHOHYDQWLQIRUPDWLRQVXFKDV$(VDQGFRQFRPLWDQW
PHGLFDWLRQV
F
7KH6DIHW\)ROORZ8S9LVLW6)8VKRXOGEHVFKHGXOHGZHHNVKDOIOLYHVDIWHUWKHODVW,03
DGPLQLVWUDWLRQ
G
3DWLHQWVZKRZLWKGUDZH[FHSWIRUWKRVHZKRZLWKGUDZWKHLUFRQVHQWZLOOEHDVNHGWRDWWHQGD:LWKGUDZDO
9LVLWDVVRRQDVSRVVLEOH
H
,IWKHGDWHRIDFOLQLFYLVLWRUSKRQHFRQWDFWGRHVQRWFRQIRUPWRWKHVFKHGXOHVXEVHTXHQWYLVLWVVKRXOGEH
SODQQHGWRPDLQWDLQWKHYLVLWVFKHGXOHUHODWLYHWRWKH%DVHOLQH9LVLW'D\9LVLW
I
$W6FUHHQLQJ9LVLWWKHSDWLHQWZLOOEHDVNHGWRVLJQWKHPDLQ,QIRUPHG&RQVHQW)RUPDQGWKH,QIRUPHG
&RQVHQW)RUPIRUEORRGVDPSOLQJIRUSKDUPDFRJHQHWLFVRSWLRQDO8QGHUH[FHSWLRQDOFLUFXPVWDQFHVVXFKDV
ZKHUH&29,'SDQGHPLFUHVWULFWLRQVLPSDFWWKHDELOLW\WRSHUIRUPVLWHYLVLWVWKHGLVFXVVLRQZLWKWKH
SDWLHQWVDERXWWKH,QIRUPHG&RQVHQW)RUPVFDQEHGRQHDVDYLUWXDOFOLQLFYLVLWDQGWKH,QIRUPHG&RQVHQW
)RUPVFDQEHSURYLGHGUHPRWHO\5HIHUWRVHFWLRQ
J
$W6FUHHQLQJ9LVLWWKHSDWLHQWZLOOEHDVNHGWRFRQILUPFRQVHQWE\UHVLJQLQJHDFKRIWKH,QIRUPHG&RQVHQW
)RUPVVLJQHGDW6FUHHQLQJ9LVLWVHSDUDWHVLJQDWXUHOLQHVRQHDFKIRUP
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
K
3DWLHQWVPXVWKDYHDGHTXDWHO\GRFXPHQWHGUHFRUGVRUUHOLDEOHKLVWRU\RIHSLVRGLFFOXVWHUKHDGDFKHKLVWRU\
DQGSUHYLRXVWUHDWPHQWIRUHSLVRGLFFOXVWHUKHDGDFKHZLWKLQWKHPRQWKVSULRUWR6FUHHQLQJ9LVLW6HH
SURWRFROIRUGHILQLWLRQRIDGHTXDWHO\GRFXPHQWHGUHFRUGV
L
3DWLHQWVZKRPHHWLQFOXVLRQFULWHULDDQGQRQHRIH[FOXVLRQFULWHULD
$W6FUHHQLQJ9LVLWWKHLQYHVWLJDWRUPXVWFRQVLGHUH[FOXGLQJSDWLHQWVZLWKDOLIHWLPHKLVWRU\RI
SV\FKRVLVELSRODUPDQLDRUGHPHQWLD3DWLHQWVZLWKRWKHUSV\FKLDWULFFRQGLWLRQVZKRVHV\PSWRPVDW
6FUHHQLQJ9LVLWDUHQRWFRQWUROOHGRUZKRKDYHQRWEHHQDGHTXDWHO\WUHDWHGPXVWEHLGHQWLILHGDQGWKH
LQYHVWLJDWRUVKRXOGFRQVLGHULQLWLDWLRQRIDSSURSULDWHWUHDWPHQWDVPHGLFDOO\LQGLFDWHG
3DWLHQWVZLWKXQFRQWUROOHGK\SHUWHQVLRQDW6FUHHQLQJ9LVLWPXVWEHLGHQWLILHGDQGWKHLQYHVWLJDWRUPXVW
FRQVLGHULQLWLDWLRQRIDSSURSULDWHWUHDWPHQWDVPHGLFDOO\LQGLFDWHGDW
6FUHHQLQJ9LVLWDUHHOLJLEOHWRHQWHU6FUHHQLQJ3HULRG3DWLHQWVZKRPHHWDOORIWKHLQFOXVLRQDQGQRQHRI
WKHH[FOXVLRQFULWHULDDWWKH6FUHHQLQJ9LVLWDQG%DVHOLQH9LVLW'D\9LVLWDUHHOLJLEOHWRSDUWLFLSDWHLQ
WKLVVWXG\
M
'XULQJWKH3ODFHERFRQWUROOHG3HULRGH352VZKLFKDUHVFKHGXOHGLQDOLJQPHQWZLWKDFOLQLFYLVLWPXVWEH
FRPSOHWHGLQWKHFOLQLFH352VZKLFKDUHVFKHGXOHGLQDOLJQPHQWZLWKDSKRQHFRQWDFWPXVWEHFRPSOHWHGLQ
WKHUHPRWHVHWWLQJRQWKHGD\RIWKHVFKHGXOHGSKRQHFRQWDFWGDWH'XULQJWKH$FWLYH7UHDWPHQW3HULRGDQG
3RVWWUHDWPHQW2EVHUYDWLRQDO3HULRGH352VZKLFKDUHVFKHGXOHGLQDOLJQPHQWZLWKDFOLQLFYLVLWFDQEH
FRPSOHWHGLQWKHFOLQLFRULQWKHUHPRWHVHWWLQJZLWKLQGD\SULRUWRWKHVFKHGXOHGFOLQLFYLVLWGDWHH352V
ZKLFKDUHVFKHGXOHGLQDOLJQPHQWZLWKDSKRQHFRQWDFWPXVWEHFRPSOHWHGLQWKHUHPRWHVHWWLQJDQGFDQEH
FRPSOHWHGRQWKHGD\RUZLWKLQGD\SULRUWRWKHVFKHGXOHGSKRQHFRQWDFWGDWH+&58DQG:3$,*+
PXVWEHDGPLQLVWHUHGDWVLWH
N $WWKH6FUHHQLQJ9LVLWWKHSDWLHQWPXVWEHDVVLVWHGZLWKWKHSURYLVLRQLQJDQGWUDLQLQJRIWKHH'LDU\DQG
H352V'HWDLOVZLOOEHSURYLGHGLQDVHSDUDWHWUDLQLQJPRGXOH
O3DWLHQWVPXVWFRPSOHWHWKHH'LDU\IURPWKHILUVWGD\RI6FUHHQLQJ3HULRGXQWLOWKH&RPSOHWLRQ9LVLW:HHN
9LVLW
P 3DWLHQWVPXVWFRPSOHWHWKHGDLO\H'LDU\DQGH352HQWULHVSULRUWRLQIXVLRQ
Q ,QDGGLWLRQWRWKHH'LDU\FRPSOLDQFHFKHFNVSHUIRUPHGDWWKHGHILQHGFOLQLFYLVLWVDQGSKRQHFRQWDFWV
RQJRLQJHYDOXDWLRQRIH'LDU\FRPSOLDQFHZLOOEHSHUIRUPHGE\WKHVLWHEDVHGRQH'LDU\UHSRUWLQJDQGPRUH
IUHTXHQWFRQWDFWZLWKSDWLHQWVPD\EHSHUIRUPHGLQFDVHRIQRQFRPSOLDQFH
R $W,03YLVLWVWZREORRGVDPSOHVZLOOEHFROOHFWHGIRU,03TXDQWLILFDWLRQDQGH[SORUDWRU\ELRPDUNHUV± RQH
SULRUWRWKH,03LQIXVLRQDQGRQH RQHKRXUDIWHUWKHHQGRIWKHLQIXVLRQ
S
,QIXVLRQ5HODWHG5HDFWLRQVPXVWEHFKHFNHGDVSDUWRIWKHRYHUDOO$(FROOHFWLRQDIWHULQIXVLRQDQGEHIRUHWKH
SDWLHQWLVGLVFKDUJHGIURPWKHVLWH
T
,QIXVLRQPXVWEHSUHFHGHGE\WKHDVVHVVPHQWRIYLWDOVLJQVLQFOXGLQJERG\WHPSHUDWXUHFRQFRPLWDQW
PHGLFDWLRQV$(V(&*EORRGVDPSOLQJIRUFOLQLFDOVDIHW\ODERUDWRU\WHVWVDQG$'$XULQHVDPSOLQJIRU
FOLQLFDOVDIHW\ODERUDWRU\DQGSUHJQDQF\WHVWVDQG&66569LWDOVLJQVPXVWEHDVVHVVHGSULRUWREORRG
VDPSOLQJ
U
9LWDOVLJQVLQFOXGLQJERG\WHPSHUDWXUHDQG$(VPXVWEHFKHFNHGDIWHULQIXVLRQ9LWDOVLJQVPXVWEHDVVHVVHG
SULRUWREORRGVDPSOLQJ
V$W6FUHHQLQJ9LVLWRQO\YLWDOVLJQVDQGZHLJKWDUHDVVHVVHG,WLVUHFRPPHQGHGWRFDOFXODWH%0,DW
6FUHHQLQJ9LVLWWRDVVHVV([FOXVLRQ&ULWHULRQLQSUHSDUDWLRQIRUWKHHOLJLELOLW\DVVHVVPHQWRI%0,DW
6FUHHQLQJ9LVLW
W
3K\VLFDODQG1HXURORJLFDOH[DPLQDWLRQVIRUDOOFOLQLFYLVLWVH[FHSW6FUHHQLQJ9LVLWZKLFKLVPDQGDWRU\
DUHWREHFRQGXFWHGDWWKHGLVFUHWLRQRIWKHLQYHVWLJDWRU,IWKHVHH[DPLQDWLRQVDUHFRQGXFWHGDWDQ,03
LQIXVLRQ9LVLWWKHVHPXVWEHSHUIRUPHGSULRUWRWKHLQIXVLRQ
X &6656ZLOOEHDGPLQLVWHUHGE\WKHDXWKRUL]HGUDWHUDWWKHFOLQLF
Y %LREDQNPD\EHH[FOXGHGRURSWLRQDOSHUORFDOUHJXODWLRQ
Z ([SORUDWRU\JHQHH[SUHVVLRQSURILOLQJ51$DQGPHWDERORPLFVSURWHRPLFVLQFOXGLQJEORRGVDPSOLQJIRU
SRVVLEOHIXWXUH$'$DVVHVVPHQWDQGIXWXUHH[SORUDWRU\ELRPDUNHUVLVFRYHUHGE\WKHPDLQ,QIRUPHG
&RQVHQW)RUP
[
6DPSOLQJIRUSKDUPDFRJHQHWLFVLVRSWLRQDODQGFRYHUHGE\DVHSDUDWH,QIRUPHG &RQVHQW
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
\
%ORRGVDPSOHVIRUVHUXPVHSDUDWLRQDQGSRVVLEOHIXWXUH$'$DQDO\VHVZLOOEHGUDZQDW%DVHOLQH'D\9LVLW
&RPSOHWLRQ:HHN9LVLW6DIHW\)ROORZ8S9LVLWRUWKH:LWKGUDZDO9LVLWLIWKHSDWLHQW
ZLWKGUDZV
] %ORRGVDPSOHVIRU$'$DW%DVHOLQH'D\9LVLWZLOOEHFROOHFWHGSULRUWRWKH,03LQIXVLRQ
DD $QXQEOLQGHGSKDUPDFLVWRUGHVLJQHHLVUHVSRQVLEOHIRUUHFHLYLQJVWRULQJDQGSUHSDULQJ,037KHSKDUPDFLVW
RUGHVLJQHHZLOOQRWEHUHVSRQVLEOHIRURWKHUDVSHFWVRIWKHFOLQLFDOVWXG\ZKHUHEOLQGLQJLVQHFHVVDU\
EE 3DWLHQWVPXVWEHPRQLWRUHGGXULQJWKHLQIXVLRQDQGIRUDSHULRGRIKRXUIURPWKHHQGRILQIXVLRQ3DWLHQWV
ZLOOEHUHTXHVWHGWRVWD\ORQJHUVKRXOGWKHLQYHVWLJDWRURUGHVLJQHHGHWHUPLQHWKLVLVFOLQLFDOO\ZDUUDQWHG
FF $GHVLJQDWHGXQEOLQGHG&5$LVUHVSRQVLEOHIRUWKH,03DFFRXQWDELOLW\
GG 7KHH'LDU\FORVHRXWZLOOWDNHSODFHDW&RPSOHWLRQ:HHN9LVLW:LWKGUDZDO9LVLWIRUSDWLHQWVZKR
ZLWKGUDZ'HWDLOVZLOOEHSURYLGHGLQDVHSDUDWHWUDLQLQJPRGXOH
HH )RUZRPHQRIFKLOGEHDULQJSRWHQWLDOSUHJQDQF\WHVWDW6FUHHQLQJ9LVLWDQGWKH6DIHW\)ROORZXS9LVLWLVWR
EHFRQGXFWHGXVLQJVHUXPȕ+&*$WDOORWKHUYLVLWVXULQHSUHJQDQF\WHVWLQJZLOOEHSHUIRUPHGDQGLQFDVH
RIDSRVLWLYHILQGLQJIXUWKHUFRQILUPDWRU\WHVWLQJZLOOEHSHUIRUPHGYLDVHUXPȕ+&*
JJ )RUSDWLHQWVZKRHQWHUWKHVWXG\DOUHDG\LQFOXVWHUKHDGDFKHERXW6FUHHQLQJ9LVLWDQG6FUHHQLQJ9LVLW
PD\EHFRPELQHGWRFDSWXUHDOODVVHVVPHQWVIRU6FUHHQLQJ9LVLWDQG6FUHHQLQJ9LVLWRQWKHVDPHGD\
KK $GYHUVHHYHQWVVHULRXVDQGQRQVHULRXVPXVWEHFROOHFWHGUHFRUGHGDQGUHSRUWHGWR/XQGEHFNIURPWKH
WLPHWKHSDWLHQWKDVVLJQHGUHVLJQHGWKHLQIRUPHGFRQVHQWIRUPVDW6FUHHQLQJ9LVLW
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Appendix V
Adverse Events of Special Interest
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Adverse Events of Special Interest
Table 5
Adverse Events of Special Interest
Event types
SMQ/HLT/HLGT
Additional criteria
&DUGLRFHUHEURYDVFXODUHYHQWV
&DUGLDFDUUK\WKPLDV604
1DUURZ
&DUGLDFIDLOXUH6041DUURZ
&DUGLRP\RSDWK\6041DUURZ
&HQWUDOQHUYRXVV\VWHPYDVFXODU
GLVRUGHUV6041DUURZ
(PEROLFDQGWKURPERWLFHYHQWV
6041DUURZ
+\SHUWHQVLRQ6041DUURZ
,VFKDHPLFKHDUWGLVHDVH604
1DUURZ
3XOPRQDU\K\SHUWHQVLRQ604
1DUURZ
7RUVDGHGHSRLQWHV47SURORQJDWLRQ
6041DUURZ
(YHQWVDVVRFLDWHGZLWK6XLFLGH
6XLFLGHVHOILQMXU\6041DUURZ
(YHQWVSRWHQWLDOO\DVVRFLDWHGZLWK
6WXG\'UXJ,QIXVLRQ
$QJLRHGHPDDQGXUWLFDULD+/*7
SULPDU\37VRQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHGRUGXULQJWKH
GD\VDIWHUGRVLQJ
%URQFKLDOGLVRUGHUVH[FO
QHRSODVPV+/*7SULPDU\37V
RQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHG
,QIXVLRQVLWHUHDFWLRQV+/7
SULPDU\37VRQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHGRUGXULQJWKH
GD\VDIWHUGRVLQJ
2UDOVRIWWLVVXHVLJQVDQGV\PSWRPV
+/7SULPDU\37VRQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHG
2UDOVRIWWLVVXHVZHOOLQJDQG
RHGHPD+/7SULPDU\37VRQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHG
3UXULWXV1(&+/7SULPDU\37V
RQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHGRUGXULQJWKH
GD\VDIWHUGRVLQJ
5DVKHVHUXSWLRQVDQGH[DQWKHPV
1(&+/7SULPDU\37VRQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHGRUGXULQJWKH
GD\VDIWHUGRVLQJ
5HVSLUDWRU\GLVRUGHUV1(&+/*7
SULPDU\37VRQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHG
5HVSLUDWRU\WUDFWVLJQVDQG
V\PSWRPV+/*7SULPDU\37V
RQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHG
8SSHUUHVSLUDWRU\WUDFWGLVRUGHUV
H[FOLQIHFWLRQV+/*7SULPDU\
37VRQO\
7($(RQWKHGD\RIGRVLQJDIWHUWKH
LQIXVLRQZDVVWDUWHG
Y 
&/,B


+/XQGEHFN$6
&RQILGHQWLDO
6WXG\ $± 6WDWLVWLFDO$QDO\VLV3ODQ
3DJH RI
Event types
SMQ/HLT/HLGT
Additional criteria
+HSDWLFHYHQWV
'UXJUHODWHGKHSDWLFGLVRUGHUV
FRPSUHKHQVLYHVHDUFK604
1DUURZ
+\SHUVHQVLWLYLW\DQG$QDSK\ODFWLF
5HDFWLRQV
$QDSK\ODFWLFUHDFWLRQ604
1DUURZ
$QJLRHGHPD6041DUURZ
+\SHUVHQVLWLYLW\6041DUURZ
6HL]XUHV
&RQYXOVLRQV6041DUURZ
Y 
&/,B