A Randomized, Double-Blind, Placebo-Controlled Study of Galcanezumab in Adults With Treatment-Resistant Migraine - the CONQUER Study
Phase: PHASE3
Conditions: Migraine
Sponsor: Eli Lilly and Company

I5Q-MC-CGAW Clinical Protocol  
 
 
A Randomized, Double-Blind, Placebo-Controlled Study of Galcanezumab in Adults with 
Treatment-Resistant Migraine – the CONQUER Study  
 
 
NCT03559257  
 
 
Approval Date: 22-Mar-2018 
 
 

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galcanezumab (LY2951742)
Protocol I5Q-MC-CGAW
A Randomized, Double-Blind, Placebo-Controlled Study of 
Galcanezumab in Adults with Treatment-Resistant 
Migraine – the CONQUER Study
EudraCT Number:  2018-000600-42
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
galcanezumab (LY2951742), unless such persons are bound by a confidentiality 
agreement with Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
galcanezumab (LY2951742)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on date provided below.
Approval Date: 22-Mar-2018 GMT

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Table of Contents
Section
Page
Protocol I5Q-MC-CGAW A Randomized, Double-Blind, Placebo-
Controlled Study of Galcanezumab in Adults with Treatment-
Resistant Migraine – the CONQUER Study ........................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................22
5.1.
Overall Design .............................................................................................................22
5.2.
Number of Participants.................................................................................................24
5.3.
End of Study Definition ...............................................................................................24
5.4.
Scientific Rationale for Study Design...........................................................................24
5.5.
Justification for Dose ...................................................................................................25
6.
Study Population...............................................................................................................26
6.1.
Inclusion Criteria..........................................................................................................26
6.2.
Exclusion Criteria ........................................................................................................27
6.3.
Lifestyle Restrictions....................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatments........................................................................................................................31
7.1.
Treatments Administered .............................................................................................31
7.1.1.
Packaging and Labelling ......................................................................................31
7.1.2.
Medical Devices...................................................................................................31
7.2.
Method of Treatment Assignment ................................................................................31
7.2.1.
Selection and Timing of Doses.............................................................................32
7.3.
Blinding .......................................................................................................................32
7.4.
Dosage Modification....................................................................................................33
7.5.
Preparation/Handling/Storage/Accountability...............................................................33
7.6.
Treatment Compliance .................................................................................................33
7.7.
Concomitant Therapy...................................................................................................33
7.8.
Treatment after the End of the Study............................................................................35

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8.
Discontinuation Criteria ....................................................................................................36
8.1.
Discontinuation from Study Treatment.........................................................................36
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................36
8.1.2.
Temporary Discontinuation from Study Treatment...............................................36
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................36
8.2.
Discontinuation from the Study....................................................................................37
8.3.
Lost to Follow-Up........................................................................................................37
9.
Study Assessments and Procedures ...................................................................................38
9.1.
Efficacy Assessments...................................................................................................38
9.1.1.
Primary Efficacy Assessments .............................................................................38
9.1.2.
Secondary Efficacy Assessments..........................................................................38
9.1.3.
Appropriateness of Assessments ..........................................................................38
9.2.
Adverse Events ............................................................................................................39
9.2.1.
Serious Adverse Events........................................................................................39
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................41
9.2.2.
Complaint Handling.............................................................................................41
9.3.
Treatment of Overdose.................................................................................................41
9.4.
Safety...........................................................................................................................41
9.4.1.
Electrocardiograms ..............................................................................................41
9.4.2.
Vital Signs ...........................................................................................................41
9.4.3.
Laboratory Tests ..................................................................................................42
9.4.4.
Immunogenicity Assessments ..............................................................................42
9.4.5.
Safety Monitoring ................................................................................................42
9.4.5.1.
Hepatic Safety Monitoring..............................................................................42
9.5.
Pharmacokinetics .........................................................................................................43
9.6.
Pharmacodynamics ......................................................................................................43
9.7.
Genetics .......................................................................................................................43
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................43
9.8.
Biomarkers...................................................................................................................44
9.9.
Health Economics ........................................................................................................44
10.
Statistical Considerations ..................................................................................................48
10.1. Sample Size Determination ..........................................................................................48
10.2. Populations for Analyses..............................................................................................48
10.3. Statistical Analyses ......................................................................................................48
10.3.1.
General Statistical Considerations ........................................................................48
10.3.2.
Treatment Group Comparability...........................................................................50
10.3.2.1.
Patient Disposition..........................................................................................50
10.3.2.2.
Patient Characteristics ....................................................................................50

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10.3.2.3.
Concomitant Therapy .....................................................................................50
10.3.2.4.
Treatment Compliance....................................................................................51
10.3.2.5.
Electronic Patient-reported Outcome Diary Compliance .................................51
10.3.3.
Efficacy Analyses ................................................................................................51
10.3.3.1.
Primary Analyses ...........................................................................................51
10.3.3.2.
Key Secondary Analyses ................................................................................52
10.3.3.3.
Other Secondary and Tertiary Analyses ..........................................................53
10.3.4.
Safety Analyses....................................................................................................53
10.3.4.1.
Treatment-Emergent Adverse Events..............................................................54
10.3.4.2.
Vital Signs......................................................................................................54
10.3.4.3.
Electrocardiogram Intervals and Heart Rate....................................................54
10.3.4.4.
Laboratory Tests.............................................................................................54
10.3.5.
Health Economics ................................................................................................55
10.3.6.
Subgroup Analyses ..............................................................................................55
10.3.7.
Interim Analyses..................................................................................................55
11.
References ........................................................................................................................57
12.
Appendices .......................................................................................................................60

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List of Tables
Table
Page
Table CGAW.1. Schedule of Activities....................................................................................11
Table CGAW.2. Objectives and Endpoints...............................................................................17
Table CGAW.3. Migraine and Headache Endpoint Definitions................................................21
Table CGAW.4. Treatments Allowed and Treatments Not Allowed as Concomitant 
Therapy .........................................................................................................34

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List of Figures
Figure
Page
Figure CGAW.1. Illustration of study design for Clinical Protocol I5Q-MC-CGAW.................22
Figure CGAW.2. Gatekeeping sequence for testing of primary and key secondary 
endpoints. ......................................................................................................53

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................61
Appendix 2.
Clinical Laboratory Tests...............................................................................64
Appendix 3.
Study Governance Considerations..................................................................65
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................70

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galcanezumab (LY2951742)
1. Synopsis
Title of Study:
A Randomized, Double-Blind, Placebo-Controlled Study of Galcanezumab in Adults with 
Treatment-Resistant Migraine – the CONQUER Study
Rationale:
The purpose of Study I5Q-MC-CGAW (CGAW) is to assess the efficacy and safety of 
galcanezumab (LY2951742) in a treatment-resistant patient population with episodic or chronic 
migraine.  There is preliminary evidence from the treatment-resistant subpopulation in the 
Phase 3 migraine studies that galcanezumab may be efficacious and well-tolerated in these 
patients. Study CGAW will include up to 6 months on galcanezumab (3 months of double-blind 
treatment and 3 months of open-label treatment).
Objectives/Endpoints:
Objectives
Endpoints
Primary Objective
To test the hypothesis that galcanezumab is 
superior to placebo in the prevention of migraine in
patients with treatment-resistant migraine
The overall mean change from baseline in the number of 
monthly migraine headache days during the 3-month 
double-blind treatment phase in the total population 
(episodic and chronic migraine)a
Key Secondary Objectives
Note:  All key secondary objectives will be tested 
in both the total population (episodic and chronic 
migraine) and the episodic migraine subpopulation 
unless otherwise specified.
The specific methodology (including testing order and 
population) for the tests of the following key secondary 
endpoints will be specified in the statistical analysis plan:

To compare galcanezumab with placebo with 
respect to prevention of migraine in the 
episodic migraine subpopulation

The overall mean change from baseline in the number 
of monthly migraine headache days during the 
3-month double-blind treatment phase in patients with 
episodic migraine

To compare galcanezumab with placebo with 
respect to 50% response rate

The percentage of patients with ≥50% reduction from 
baseline in monthly migraine headache days during the 
3-month double-blind treatment phase

To compare galcanezumab with placebo with 
respect to change in functioning

The mean change from baseline in the Role Function-
Restrictive domain score of the Migraine-Specific 
Quality of Life Questionnaire version 2.1 (MSQ v2.1) 
at Month 3

To compare galcanezumab with placebo with 
respect to 75% response rate

The percentage of patients with ≥75% reduction from 
baseline in monthly migraine headache days during the 
3-month double-blind treatment phase

To compare galcanezumab with placebo with 
respect to 100% response rate

The percentage of patients with 100% reduction from 
baseline in monthly migraine headache days during the 
3-month double-blind treatment phase
a
Episodic migraine is defined as 4 to 14 migraine headache days and <15 headache days per 30-day period in the 
prospective baseline period.  Chronic migraine is defined as at least 15 headache days per 30-day period in the 
prospective baseline period, of which at least 8 are migraine.

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Summary of Study Design:  
Study CGAW is a multicenter, randomized, double-blind, parallel, placebo-controlled study of 
galcanezumab in patients who meet International Classification of Headache Disorders (ICHD) 
criteria for a diagnosis of migraine with or without aura or chronic migraine, and who have 
previously failed 2 to 4 standard-of-care treatments for migraine prevention.  The study has 
4 periods, including a prospective baseline period to determine patient eligibility.
Treatment Arms and Duration:  
Two treatment arms:  galcanezumab (120 mg/month, with a 240-mg loading dose) and placebo.  
Following a 1-month prospective baseline period, eligible patients will be randomized in a 
1:1 ratio to receive placebo or galcanezumab for up to 3 months of double-blind treatment.  
Investigational product is administered as 1 or 2 subcutaneous injections per month (2 injections 
of 120-mg galcanezumab or 2 injections of placebo at randomization; 1 injection of 120-mg 
galcanezumab or 1 injection of placebo at the subsequent double-blind dosing visits).  Patients 
who complete the double-blind treatment phase may enter a 3-month open-label treatment phase. 
At the first dosing visit in the open-label treatment phase, patients previously assigned to placebo 
will receive an initial loading dose of galcanezumab 240 mg (2 injections of 120 mg each), while 
patients previously assigned to galcanezumab will receive 1 injection of 120-mg galcanezumab 
and 1 injection of placebo to retain blinding of dose assignment from the double-blind phase.  
Thereafter, all patients in the open-label treatment phase will receive 120 mg/month 
galcanezumab.
Number of Patients:
The study will screen an estimated 764 potential study participants to ensure randomization of 
approximately 420 patients with migraine, of which approximately 250 patients have episodic 
migraine.  
Statistical Analysis:
Unless otherwise specified, analyses will be conducted on an intent-to-treat (ITT) population, 
which includes all patients who are randomized and receive at least one dose of investigational 
product.  Patients in the ITT population will be analyzed according to the treatment group to 
which they are randomized.  When change from baseline is assessed, the patient will be included 
in the analysis only if he/she has a baseline and a postbaseline measurement.
The primary analysis will evaluate the efficacy of galcanezumab compared with placebo on the 
overall mean change from baseline in the number of monthly migraine headache days during the 
3-month double-blind treatment phase.  Migraine headache day is defined to include both 
migraine and probable migraine days.  The primary analysis will be performed using a restricted 
maximum likelihood-based mixed model repeated measures technique.

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2. Schedule of Activities

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Table CGAW.1.
Schedule of Activities
Study Period
SP I
Screening
SP II
Prospective 
Baseline
SP III
Double-Blind Treatment
SP IV
Open-Label
Treatment
ET
Notes
(Target) Interval (days) 
since previous visit
30-45
30
30
30
30
30
30
Allowable range (days) 
between visits
3-30
30-40a
Interval allowance 
(days)
±2
±2
±2
±2
±2
±2
Visit
1
2
3
4
5
6
7
8
9
Month
0
1
2
3
4
5
6
Assessments and Procedures
Informed consent
X
Inclusion/exclusion
X
X
X
Demographics
X
Physical examination
X
Neurological examination
X
X
X
Height
X
Weight
X
X
X
X
X
Medical history 
X
Substance use
X
Substances:  alcohol, caffeine, 
nicotine, tobacco
ECG
X
X
X
X
X
Predose and prior to blood draws.  
See Section 9.4.1.

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Schedule of Activities
Study Period
SP I
Screening
SP II
Prospective 
Baseline
SP III
Double-Blind Treatment
SP IV
Open-Label
Treatment
ET
Notes
Visit
1
2
3
4
5
6
7
8
9
Month
0
1
2
3
4
5
6
Vital signs
X
X
X
X
X
X
X
X
X
Includes body temperature, sitting 
blood pressure, and pulse.  
Predose and prior to blood draws.  
See Section 9.4.2.
Adverse events
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
ePRO and headache 
medication log training
X
ePRO daily patient entries
X
X
X
X
X
X
X
X
X
Headache medication log
X
X
X
X
X
X
X
X
X
Patient training video
X
Clinical Laboratory Tests and Sampling Schedule
Hematology
X
X
X
X
X
See Appendix 2.
Clinical chemistryb
X
X
X
X
X
Fasting is not required.  See 
Appendix 2.
HbA1c
X
X
X
X
Fasting is not required.  
Urinalysis
X
X
X
X
X
See Appendix 2.
In the event of a positive urine 
leukocyte esterase result, a repeat 
urine sample will be collected and 
shipped to the central laboratory.
Serum Pregnancy (for 
women of childbearing 
potential) or FSH (Visit 1 
only; all other female 
patients)
X
X
X
A positive urine test must be 
followed by a serum pregnancy 
test for confirmation.  Collect 
serum pregnancy at Visit 6 if 
patient not continuing into SP IV. 

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Schedule of Activities
Study Period
SP I
Screening
SP II
Prospective 
Baseline
SP III
Double-Blind Treatment
SP IV
Open-Label
Treatment
ET
Notes
Visit
1
2
3
4
5
6
7
8
9
Month
0
1
2
3
4
5
6
Urine pregnancy
X
X
X
X
X
X
A positive urine test must be 
followed by a serum pregnancy 
test for confirmation. Collect 
serum pregnancy at Visit 6 if 
patient not continuing into SP IV.
Urine drug screen
X
Immunogenicity storage 
samplec
X
Predose
Pharmacogenetic sample 
(genetic sample/DNA)
X
Predose
RNA
X
X
Predose
Study drug administered
X
X
X
X*
X
X
IP injections are to occur after all 
other visit procedures are 
completed.  
*Patients not entering SP IV will 
not receive IP at V6.
Scales, Questionnaires, and Outcome Measures
MIDAS
X
X
X
X
MSQ v2.1
X
X
X
X
X
X
X
X
HCRU/Employment 
Status
X
X
X
X
X
X
X
X
PGI-S
X
X
X
X
MIBS-4
X
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
WPAI
X
X
X
X
X
X
X
X
X
X
X
X
CCI
CCI

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galcanezumab (LY2951742)
Schedule of Activities
Abbreviations:  AE = adverse event; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ePRO = electronic patient-reported outcomes; EQ-5D-5L = 
European Quality of Life 5-Dimensions 5-Levels; ET = early termination; FSH = follicle stimulating hormone;
 
; HbA1c = hemoglobin A1c; HCRU = Health Care Resource Utilization questionnaire; IP = investigational product; MIBS-4 = 4-item Migraine 
Interictal Burden Scale; MIDAS = Migraine Disability Assessment; MSQ (v2.1) = Migraine-Specific Quality of Life Questionnaire version 2.1; PGI-S = 
Patient Global Impression of Severity; 
; RNA = ribonucleic acid; SP = study period; V = visit; WPAI = Work 
Productivity and Activity Impairment Questionnaire.
a
The eligibility period of the prospective baseline assessment will last from 30 to 40 days.  Investigators and patients may have up to an additional 5 days to 
schedule their Visit 3 appointment (beyond the 40 days); however, eligibility will be based on the 30- to 40-day period.
b
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may be required in follow-up with patients in consultation with 
the Lilly, or its designee, clinical research physician.  See Appendix 4 for more details regarding specific hepatic monitoring tests.  If the patient has 
discontinued the trial and returns for hepatic follow-up, the site should use the 800 series as the visit designation.
c
An immunogenicity sample may also be collected and analyzed in the event of a serious potential systemic hypersensitivity AE. Additional tests may be 
requested in order to further characterize the event and/or aid interpretation of the anti-drug antibody result.  See Section 9.4.3.
CCI
CCI
CCI

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3. Introduction
3.1.
Study Rationale
The purpose of Study I5Q-MC-CGAW (CGAW) is to assess the efficacy and safety of
galcanezumab (LY2951742) in a treatment-resistant patient population with episodic or chronic 
migraine.  Treatment resistance, in this study, will be defined as previous failure to respond to 
2 to 4 different standard-of-care migraine preventive medications either due to inadequate 
efficacy and/or due to safety/tolerability reasons (see Section 6.1 for further details).  
The efficacy and safety of galcanezumab have previously been established in three Phase 3 
clinical trials (Study I5Q-MC-CGAG [CGAG] and Study I5Q-MC-CGAH [CGAH] for episodic 
migraine and Study I5Q-MC-CGAI [CGAI] for chronic migraine). Subgroup analyses in those 
patients with at least 2 prior migraine preventive treatment failures due to efficacy alone
(prespecified) or efficacy and/or safety/tolerability reasons (post hoc) have indicated clinically 
meaningful improvements in multiple outcomes. However, the Phase 3 studies excluded patients 
who had failed medications from 3 or more classes of migraine preventives due to inadequate 
efficacy among those medications with Level A or Level B evidence (defined as those listed in 
Silberstein et al. [2012] or botulinum toxin A or B). 
Study CGAW will thus enable a comprehensive clinical assessment of galcanezumab in a
broader treatment-resistant patient population, including patients who may potentially have 
failed up to 4 different classes of standard-of-care migraine preventives. Treatment resistance is 
more prevalent among patients with chronic migraine than episodic; however, the episodic form 
of migraine (ie, 4 to 14 migraine headache days and fewer than 15 headache days per month) is 
the most common, with approximately 7% of the migraine population suffering from the chronic 
form (ie, at least 15 headache days per month, of which at least 8 are migraine) (Buse et al. 2012; 
Katsarava et al. 2012; Blumenfeld et al. 2013; ICHD-3 2018). Therefore, there is a need to 
evaluate the efficacy and safety of galcanezumab in a treatment-resistant population, as well as 
specifically address for the episodic population. Study CGAW will include up to 6 months on 
galcanezumab (3 months of double-blind treatment and 3 months of open-label treatment).
3.2.
Background
Migraine is a chronic, debilitating neurological disease found to be one of the top 10 causes of 
disability worldwide (Vos et al. 2012).  Despite the availability of preventive medications for 
migraine, many patients do not respond to these treatments or are unable to tolerate them.
Research on treatment patterns indicate that, among all preventive medication users in the United 
States, Germany, France, and Japan, approximately 43% have a history of previous preventive 
medication failure or of switching treatments (Pike et al. 2016). Among patients with episodic or 
chronic migraine who are undergoing oral preventive treatment, side effects and a lack of 
efficacy are the most common reasons for discontinuation (Blumenfeld et al. 2013). Among 
patients whose disease is not adequately managed, the negative impact on patient functioning 
increases, leading to losses in work/school and home productivity, missing or restricting family 
and social activities, and an overall decrease in quality of life (Blumenfeld et al. 2011; Lantéri-
Minet et al. 2011; Bagley et al. 2012; Abu Bakar et al. 2016). Another indicator of the disabling 

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galcanezumab (LY2951742)
nature of the inadequate treatment of migraine is health care resource utilization (Shah et al. 
2013; Messali et al. 2016). The number of outpatient visits is greater among patients with 
migraine compared to patients without migraine, and the direct costs associated with health care 
resource utilization are even greater among patients with a history of switching and 
discontinuing multiple migraine preventive treatments (Bonafede et al. 2017; Ford et al. 2017; 
Raval and Shah 2017).  Therefore, new treatment options are needed, particularly for those 
patients who have previously failed multiple preventive medications.
Calcitonin gene-related peptide (CGRP) is a 37-amino acid neuropeptide widely expressed 
throughout the central and peripheral nervous system.  Calcitonin gene-related peptide is 
implicated in the pathophysiology of migraine and is hypothesized to be involved in the release 
of inflammatory mediators and the transmission of nociceptive (pain) information from 
intracranial blood vessels to the nervous system (Villalón and Olesen 2009).  In individuals with 
migraine, serum concentrations of CGRP are significantly elevated during migraine attacks 
(Goadsby et al. 1990; Goadsby and Edvinsson 1993), and infusion of CGRP to individuals with a 
history of migraine can trigger migraine attacks (Lassen et al. 1998, 2002).  The binding of 
CGRP with antibodies has been shown to prevent its biological activity; thus, these antibodies 
represent a promising pharmacologic approach for the prevention of migraine.
3.3.
Benefit/Risk Assessment
Galcanezumab is a humanized monoclonal antibody that potently and selectively binds to CGRP
and prevents its biological activity without blocking the CGRP receptor.  The efficacy of 
galcanezumab for the prevention of migraine has been demonstrated in three Phase 3 
randomized, double-blind trials which found statistically significant and clinically meaningful 
mean reduction of monthly migraine headache days and improvement in patient function 
compared to placebo in patients with episodic and chronic migraine. Across Phase 2 and Phase 3 
clinical studies in patients with migraine, galcanezumab exhibited a favorable safety profile at 
doses up to 300 mg every 4 weeks for 3 months, or 240 mg monthly for up to 1 year. The 
incidences of serious adverse events (SAEs) and discontinuations due to adverse events (AEs) 
were low, and treatment-emergent adverse events (TEAEs) were generally of mild to moderate 
severity.  In the Phase 3 studies, the most commonly reported TEAEs were injection site pain 
and injection site reactions, also generally of mild to moderate severity. There was no evidence 
of an effect on cardiovascular function. These data provide a favorable benefit-risk profile for 
galcanezumab for migraine prevention.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of galcanezumab are to be found in the Investigator’s Brochure (IB).

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galcanezumab (LY2951742)
4.
Objectives and Endpoints
Table CGAW.2 shows the objectives and endpoints of the study.  Table CGAW.3 provides 
migraine and headache endpoint definitions.
Table CGAW.2.
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To test the hypothesis that galcanezumab is 
superior to placebo in the prevention of migraine in
patients with treatment-resistant migraine
The overall mean change from baseline in the number of 
monthly migraine headache days during the 3-month double-
blind treatment phase in the total population (episodic and 
chronic migraine)a
Key Secondary Objectives
Note:  All key secondary objectives will be tested 
in both the total population (episodic and chronic 
migraine) and the episodic migraine subpopulation 
unless otherwise specified.
The specific methodology (including testing order and 
population) for the tests of the following key secondary 
endpoints will be specified in Section 10.3.3.2 and the 
statistical analysis plan:  

To compare galcanezumab with placebo with 
respect to prevention of migraine in the 
episodic migraine subpopulation

The overall mean change from baseline in the number of 
monthly migraine headache days during the 3-month 
double-blind treatment phase in patients with episodic 
migraine

To compare galcanezumab with placebo with 
respect to 50% response rate

The percentage of patients with ≥50% reduction from 
baseline in monthly migraine headache days during the 
3-month double-blind treatment phase

To compare galcanezumab with placebo with 
respect to change in functioning

The mean change from baseline in the Role Function-
Restrictive domain score of the Migraine-Specific Quality 
of Life Questionnaire version 2.1 (MSQ v2.1) at Month 3

To compare galcanezumab with placebo with 
respect to 75% response rate

The percentage of patients with ≥75% reduction from 
baseline in monthly migraine headache days during the 
3-month double-blind treatment phase

To compare galcanezumab with placebo with 
respect to 100% response rate

The percentage of patients with 100% reduction from 
baseline in monthly migraine headache days during the 
3-month double-blind treatment phase

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galcanezumab (LY2951742)
Objectives and Endpoints
Objectives
Endpoints
Other Secondary Objectives
Note:  All other secondary objectives will be tested 
in both the total population (episodic and chronic 
migraine) and the episodic migraine subpopulation 
unless otherwise specified.

To compare galcanezumab with placebo with 
respect to onset of effect

The initial month at which statistical separation in mean 
change from baseline in the number of monthly migraine 
headache days is demonstrated and maintained at all 
subsequent months through Month 3 in the double-blind 
treatment phase

If the initial month of onset is Month 1, then the initial 
week at which statistical separation in mean change from 
baseline in the number of weekly migraine headache days 
is demonstrated and maintained at all subsequent weeks 
during Month 1

To compare galcanezumab with placebo with 
respect to change in use of acute headache
treatment

The overall mean change from baseline in the number of 
monthly days with acute headache medication use during 
the 3-month double-blind treatment phase

To compare galcanezumab with placebo with 
respect to change in monthly headache days

The overall mean change from baseline in the number of 
monthly headache days during the 3-month double-blind 
treatment phase

To compare galcanezumab with placebo with 
respect to change in International 
Classification of Headache Disorders (ICHD) 
migraine headache days

The overall mean change from baseline in the number of 
monthly International Classification of Headache 
Disorders (ICHD) migraine headache days during the 
3-month double-blind treatment phase

To compare galcanezumab with placebo with 
respect to change in monthly migraine
headache hours

The overall mean change from baseline in the number of 
monthly migraine headache hours during the 3-month 
double-blind treatment phase

To compare galcanezumab with placebo with 
respect to change in monthly headache hours 

The overall mean change from baseline in the number of 
monthly headache hours during the 3-month double-blind 
treatment phase

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galcanezumab (LY2951742)
Objectives and Endpoints
Objectives
Endpoints
Other Secondary Objectives (continued)

To compare galcanezumab with placebo with 
respect to changes in disability and quality of 
life

Changes from baseline to Month 3 on the following 
measures:

Migraine Disability Assessment test (MIDAS) total score 
and individual items

MSQ v2.1 total score, and Role Function-Preventive and 
Emotional Function domain scores

Health Care Resource Utilization (HCRU) and 
Employment Status

European Quality of Life Questionnaire 5-Dimensions
5-Levels (EQ-5D-5L) 

4-item Migraine Interictal Burden Scale (MIBS-4)

Work Productivity and Activity Impairment 
Questionnaire (WPAI)

To compare galcanezumab with placebo with 
respect to change in patient global impression 
of the severity of migraine

Mean change from baseline in the Patient Global 
Impression of Severity (PGI-S) at Month 3

To compare galcanezumab with placebo with 
respect to changes in migraine attacks 
(episodic migraine subpopulation only)

The overall mean change from baseline in the number of 
monthly migraine attacks during the 3-month double-
blind treatment phase in patients with episodic migraine

To compare galcanezumab with placebo with 
respect to 30% response rate 
(chronic migraine subpopulation only)

The percentage of chronic migraine patients with ≥30% 
reduction from baseline in monthly migraine headache
days during the 3-month double-blind treatment phase

To compare galcanezumab with placebo with 
respect to safety and tolerability

Analysis of:
o
treatment-emergent adverse events (TEAEs)
o
serious adverse events (SAEs)
o
discontinuation due to adverse events (AEs)
o
discontinuation rates
o
vital signs and weight
o
electrocardiograms (ECGs)
o
laboratory measures

To assess changes in efficacy, safety, and 
functional outcomes during Study Period IV
(open-label treatment)

In Study Period IV:
o
Mean changes in all continuous measures of efficacy, 
safety, and functional outcomes that are also assessed 
in the double-blind phase
o
Among patients previously treated with 
galcanezumab who meet 50% response criteria at 
Month 3 in the double-blind treatment phase, the 
proportion of patients who demonstrate 50% 
response for all 3 months in the open-label treatment 
phase

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Objectives and Endpoints
Objectives
Endpoints
Tertiary Objectives
Note:  All tertiary objectives will be tested in both 
the total population (episodic and chronic 
migraine) and the episodic migraine subpopulation.

To compare galcanezumab with placebo with 
respect to changes in symptoms associated 
with migraine 

Change from baseline in the number of monthly migraine 
headache days with:
o
nausea and/or vomiting
o
photophobia and phonophobia
o
aura
o
prodromal symptoms 

Change from baseline in the number of monthly 
symptom-free days and headache-free days

 
 

 

To explore use of comfort measures at the 
injection site

Descriptive summary of comfort measures used 
a
Episodic migraine is defined as 4 to 14 migraine headache days and <15 headache days per 30-day period in the 
prospective baseline period.  Chronic migraine is defined as at least 15 headache days per 30-day period in the 
prospective baseline period, of which at least 8 are migraine.
CCI
CCI

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Table CGAW.3.
Migraine and Headache Endpoint Definitions
Diagnosis
Definition/Criteria
Migraine headache
A headache, with or without aura, of ≥30 minutes duration, with both of the 
following required features (A and B):
A.  At least 2 of the following headache characteristics:

Unilateral location

Pulsating quality

Moderate or severe pain intensity

Aggravation by or causing avoidance of routine physical activity
AND
B.  During headache at least one of the following:

Nausea and/or vomiting

Photophobia and phonophobia
(Definition adapted from the standard IHS ICHD-3 definition)
Probable migraine headache
A headache of ≥30 minutes duration, with or without aura, but missing one of the 
migraine features in the IHS ICHD-3 definition.  To be exact, it meets either at 
least two A criteria and zero B criteria, or one A criteria and at least one B 
criteria.
Migraine headache day 
(primary objective)
A calendar day on which a migraine headache or probable migraine headache 
occurs.
ICHD migraine headache day
A calendar day on which a migraine headache occurs.
Migraine headache attack
Beginning on any day a migraine headache or probable migraine headache is 
recorded and ends when a migraine-free day occurs.
Non-migraine headache
All headaches of ≥30 minutes duration not fulfilling the definition of migraine or 
probable migraine.
Non-migraine headache day
A calendar day on which a non-migraine headache occurs.
Headache day
A calendar day on which any type of headache occurs (including migraine, 
probable migraine, and non-migraine headache).
Episodic migraine
Four to 14 migraine headache days and <15 headache days per 30-day period in 
the prospective baseline period.
Chronic migraine
At least 15 headache days per 30-day period in the prospective baseline period, 
of which at least 8 are migraine.
Abbreviations:  ICHD = International Classification of Headache Disorders; IHS = International Headache Society.

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5. Study Design
5.1.
Overall Design
Study CGAW is a Phase 3, multicenter, randomized, double-blind, parallel, placebo-controlled 
study of galcanezumab in patients who meet International Headache Society (IHS) International 
Classification of Headache Disorders – 3rd edition (ICHD-3) criteria for a diagnosis of migraine 
with or without aura or chronic migraine, and have a history of 2 to 4 prior migraine preventive 
treatment failures due to inadequate efficacy or tolerability.  The study has 4 periods, including a 
prospective baseline period to determine patient eligibility.  
Study governance considerations are described in detail in Appendix 3.
Figure CGAW.1 illustrates the study design.  
Abbreviation: SP = study period.
a  Eligibility period determined between a minimum of 30 days and a maximum of 40 
days, with up to 5 additional days to schedule randomization visit, if necessary. 
b  Patients randomized to galcanezumab will receive a loading dose of 240 mg at the 
first injection only (Visit 3).
c   Patients randomized to placebo who enter SP IV will receive a loading dose of 
galcanezumab 240 mg at the first injection only of SP IV (Visit 6). 
d  First injection of the open-label treatment phase will occur at Visit 6 once all study 
procedures for the double-blind phase are completed.
Figure CGAW.1.
Illustration of study design for Clinical Protocol I5Q-MC-CGAW.
Study Period I:  The study and potential risks will be explained to the patient at Visit 1.  The 
informed consent form (ICF) must be signed before any study procedures are performed.  

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Patients are required to discontinue all excluded medications or treatments for migraine 
prevention at least 5 days prior to Visit 2.  Botulinum toxin A or B in the head or neck area for 
therapeutic use must be discontinued at least 3 months prior to Visit 2.  Nerve blocks or device 
use, such as transcranial magnetic stimulation, in the head or neck area or for migraine 
prevention are not allowed within 30 days before Visit 2.  
The screening visit (Visit 1) will consist of a full clinical assessment, including a comprehensive 
medical evaluation documenting medical history, and a physical and neurological examination 
(see Schedule of Activities, Section 2).  Visit 1 will be complete when the last scheduled 
procedure of the screening assessment for the patient is completed.  
Study Period II:  Qualified patients will enter Study Period II (prospective baseline) to 
determine their eligibility for the study and to establish baseline data for comparison of endpoints 
during the double-blind treatment phase.  Beginning at Visit 2, patients will log in daily to the 
electronic patient-reported outcomes (ePRO) system to answer questions about the occurrence of 
headaches, headache duration, headache features, severity of headache, and whether any acute
headache medication was taken.  Also beginning at Visit 2, patients will record the name, dose, 
and date of any acute headache medication on a headache medication log which will be returned 
to site staff at each study visit.  At the end of the prospective baseline period, sites will be 
notified whether their patients met criteria and are eligible to be randomized at Visit 3.
To avoid biased reporting, patients must not be told the number of migraine or headache 
days on which study qualification is based.
Study Period III:  At the start of the 3-month double-blind treatment phase (Visit 3), patients 
meeting all eligibility requirements will be randomized in a 1:1 ratio to receive 120 mg/month 
galcanezumab (with an initial 240-mg loading dose) or placebo.  At Visit 3, if available and 
where local regulations and ethical review boards (ERBs) allow, patients will also watch a 
training video designed to address patient expectations with regard to participation in a placebo-
controlled trial and the difference between medical treatment and research.  To preserve 
blinding, patients in both treatment groups will receive 2 injections of investigational product at 
the first dosing visit (2 galcanezumab injections of 120 mg or 2 placebo injections) and then 
1 injection of investigational product (120-mg galcanezumab or placebo) for the next 2 dosing 
visits.
The patient will be considered enrolled in the study when randomization occurs.  During this 
phase, study procedures at dosing visits must always occur prior to the patient receiving their 
assigned treatment.  
Patients will be given investigational product (galcanezumab or placebo) injections during office 
visits (Figure CGAW.1).  For both treatment groups, investigational product will be administered 
by subcutaneous injection once monthly at the dosing visits.  Patients will continue to log in and 
complete the ePRO diary each day.  Patients may continue to take their allowed acute migraine 
headache medication (with some limitations; see Section 7.7) during the treatment phase and will 
continue to record this use. 

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Patients will receive their last double-blind dose of investigational product at Visit 5.  Patients 
who do not opt to continue into Study Period IV will receive no further injections.
Study Period IV:  Patients who complete the double-blind treatment phase (Study Period III) 
can opt to enter an open-label treatment phase (Study Period IV) for 3 months of treatment with 
galcanezumab.  Sites and patients will remain blinded to patients’ previous treatment 
assignments.  In order to preserve that blind but to allow for a loading dose to be administered to 
previous placebo patients, all patients who enter the open-label treatment phase will receive 
2 injections at Visit 6, and sites and patients will remain blinded to the dose administered at 
Visit 6; patients previously assigned to galcanezumab will receive 1 injection of 120 mg and 
1 injection of placebo, while those patients previously assigned to placebo will receive an initial 
loading dose of galcanezumab 240 mg (2 injections of 120 mg each).  Injections administered 
after Visit 6 will be unblinded to dose as all patients will be receiving 120 mg/month 
galcanezumab at the next 2 dosing visits (Visit 7 and Visit 8).  Patients will continue to have 
efficacy and safety assessed, including daily completion of the ePRO diary and recording of 
acute headache medication use (see Schedule of Activities, Section 2).  
5.2.
Number of Participants
The study will screen an estimated 764 potential study participants to ensure randomization of 
approximately 420 patients with migraine, of which approximately 250 patients have episodic 
migraine (defined as 4 to 14 migraine headache days and <15 headache days per 30-day period 
in the prospective baseline period).  To ensure an appropriate balance of patients with episodic 
and chronic migraine, the sponsor will stop enrollment of patients with chronic migraine if the 
number of patients exceeds approximately 40%.  Chronic migraine will be defined as at least 
15 headache days per 30-day period in the prospective baseline period, of which at least 8 are 
migraine. Further details are available in Section 10.1.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
The length of the randomized, double-blind treatment phase (3 months) is considered a sufficient 
duration to demonstrate the efficacy of a migraine preventive medication versus placebo given 
the mechanism and observed onset of action for CGRP antibodies (Dodick et al. 2014a, 2014b).  
Furthermore, a placebo-controlled study with a duration longer than 3 months may not be 
tolerated by patients suffering from chronic migraine.  A 3-month open-label extension is 
included to allow for assessment of maintenance of effect and longer-term safety.  
The use of a placebo-controlled study is considered to be appropriate, as major treatment 
guidelines rely on placebo-controlled data as the gold standard for establishing levels of evidence 
in support of treatment efficacy (eg, European Federation of Neurological Societies [Evers et al.
2009], American Academy of Neurology [Silberstein et al. 2012]).  

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5.5.
Justification for Dose
In the adult Phase 3 migraine studies, the dose regimen of 120 mg/month with a 240-mg loading 
dose was found to be efficacious and safe for the prevention of migraine in adult patients.  A 
loading dose of 240 mg resulted in achievement of steady-state concentrations for the 120-mg 
monthly maintenance dose by Month 1.  

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6.
Study Population
All patients must meet the following selection criteria.  Eligibility of patients for study 
enrollment will be based on the results of a screening medical history, physical examination, 
neurological examination, clinical laboratory tests, electrocardiograms (ECGs), and migraine 
history during screening and a prospective baseline period, as described in Sections 6.1 and 6.2.  
The nature of any comorbid conditions present at the time of the physical examination and any 
pre-existing conditions must be documented.  Individuals who do not meet the criteria for 
participation in this study (screen failure) for specific reasons as outlined may be considered for 
rescreening once, with approval from Eli Lilly and Company (Lilly) Medical (see Section 6.4).
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening:
Patient and Disease Characteristics
[1]
Patients are 18 to 75 years of age (inclusive) at the time of screening.
[2]
Have a diagnosis of migraine as defined by IHS ICHD-3 guidelines (1.1, 1.2, 
or 1.3) (ICHD-3 2018), with a history of migraine headaches of at least 1 year 
prior to Visit 1, and migraine onset prior to age 50.  
[3]
Prior to Visit 1, have a history of at least 4 migraine headache days and at 
least 1 headache-free day per month on average within the past 3 months.
[4]
Prior to Visit 1, have documentation (medical or pharmacy record or by 
physician’s confirmation) of previous failure to 2 to 4 migraine preventive 
medication categories in the past 10 years from the following list due to 
inadequate efficacy (that is, maximum tolerated dose for at least 2 months) 
and/or safety/tolerability reasons.
a) propranolol or metoprolol 
b) topiramate 
c) valproate or divalproex 
d) amitriptyline 
e) flunarizine 
f)
candesartan
g) botulinum toxin A or B (if documented that botulinum toxin was taken for 
chronic migraine)
h) medication locally approved for prevention of migraine
Note:  Patients only qualifying under the above criteria with f) and h) should 
not exceed 20% of the total study population.

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[5]
From Visit 2 to Visit 3 (prospective baseline period), have a frequency of 4 or 
more migraine headache days and at least 1 headache-free day per 30-day 
period (see definitions in Table CGAW.3).  To avoid biased reporting, 
patients will not be told the number of migraine or headache days on 
which study qualification is based.
[6]
From Visit 2 to Visit 3 (prospective baseline period), must achieve sufficient 
compliance with ePRO daily headache entries as demonstrated by completion 
of at least 80% of daily diary entries.
Informed Consent and Patient Agreements
[7]
Are able and willing to give signed informed consent.
[8]
Are reliable and willing to follow study procedures.
[9]
Women of child-bearing potential must test negative for pregnancy at the time 
of enrollment based on a serum pregnancy test.
[10] All females must agree to use a reliable method of birth control during the 
study as well as for 5 months after the last dose of investigational 
product. Acceptable methods of birth control for this study include: oral 
contraceptives; implantable contraceptives; injectable contraceptives; a 
contraceptive patch; barrier methods such as diaphragms with contraceptive 
jelly, cervical caps with contraceptive jelly, condoms with contraceptive foam, 
or intrauterine devices; or a partner with vasectomy. Birth control is not 
required if the female is infertile due to surgical sterilization (hysterectomy, or 
at least 6 weeks after surgical bilateral oophorectomy or tubal ligation) 
confirmed by medical history or menopause.  Menopause is defined as 
spontaneous amenorrhea for at least 12 months not induced by a medical 
condition, or spontaneous amenorrhea of 6-12 months and a follicle 
stimulating hormone level >40 mIU/mL.
[11] Agree not to post any personal medical data related to the study or 
information related to the study on any website or social media site (eg, 
Facebook, Twitter, LinkedIn, Google+, etc.) until the entire trial has 
completed.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening:
Prior/Concomitant Therapy
[12] Are currently enrolled in any other clinical trial involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.  

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[13] Have participated within the last 30 days or within 5 half-lives (whichever is 
longer) in a clinical trial involving an investigational product.  If the 
investigational product’s half-life is not known, 6 months should have passed 
prior to Visit 1.
[14] Prior use of galcanezumab or another CGRP antibody or CGRP receptor 
antibody, including those who have previously completed or withdrawn from 
this study.
[15] Known hypersensitivity to monoclonal antibodies or other therapeutic 
proteins, or to galcanezumab.
[16] Are currently receiving medication or other treatments for the prevention of 
migraine headaches.  Patients must have discontinued such treatment at least
5 days prior to Visit 2.  Botulinum toxin A and B that has been administered 
in the head or neck area for therapeutic use must be discontinued at least 
3 months prior to Visit 2.  Nerve blocks or device use (such as transcranial 
magnetic stimulation) in the head or neck area or for migraine prevention 
must be discontinued at least 30 days prior to Visit 2.
[17] Have previously failed more than 4 migraine preventive medication categories
from the list in Inclusion Criterion [4] due to inadequate efficacy (that is, 
maximum tolerated dose for at least 2 months) and/or safety/tolerability 
reasons.  Previous failures to medications not on the above list will not count 
toward this exclusion.
Diagnostics Assessments
[18] History of cluster headache or migraine subtypes including hemiplegic 
(sporadic or familial) migraine, ophthalmoplegic migraine, and migraine with 
brainstem aura (basilar-type migraine) defined by IHS ICHD-3. 
[19] In the 3 months prior to randomization, have other types of headache besides
migraine, tension type headache, or medication overuse headache (MOH) as 
defined by IHS ICHD-3. (In other words, patients can have migraine, tension 
type headache, or MOH in the 3 months prior to randomization, but they 
cannot have other types of headache in that time.)  
[20] History of head or neck injury within 6 months prior to Visit 1.
[21] History of traumatic head injury associated with significant change in the 
quality or frequency of their headaches.

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Medical Conditions  
[22] Have centralized reading of ECG at Visit 1 showing abnormalities compatible 
with acute cardiovascular events and/or serious cardiovascular risk, or have 
had myocardial infarction, unstable angina, percutaneous coronary 
intervention, coronary artery bypass graft, or stroke within 6 months of 
screening, or have planned cardiovascular surgery or percutaneous coronary 
angioplasty.  Fridericia-corrected QT interval (QTcF) >450 msec for males or 
>470 msec for females based on the centralized reading of the ECG at Visit 1 
must be discussed and judged not clinically significant by the principal 
investigator and Lilly Medical prior to enrollment.
[23] Any liver tests outside the normal range at Visit 1 that are clinically 
significant. Alanine aminotransferase (ALT) >2X upper limit of normal 
(ULN), or total bilirubin (TBL) >1.5X ULN, or alkaline phosphatase (ALP) 
>2X ULN must be discussed and judged not clinically significant by the 
principal investigator and Lilly Medical prior to enrollment.
[24] Evidence of significant active or unstable psychiatric disease by medical 
history, such as bipolar disorder, schizophrenia, personality disorders, or other 
serious mood or anxiety disorders.  Note:  Patients with major depressive 
disorder (MDD) or generalized anxiety disorder (GAD) whose disease state is 
considered stable and expected to remain stable throughout the course of the 
study, in the opinion of the investigator, may be considered for inclusion if 
they are not on excluded medications.
[25] Patients who, in the clinician’s judgment, are actively suicidal and therefore 
deemed to be at significant risk for suicide, or have had clinically significant 
suicidal ideation within the past month (eg, includes some plan or intent to 
act), or have had any suicidal behavior within the past month.
[26] Women who are pregnant or nursing.
[27] Patients who have used opioids or barbiturate containing analgesic >4 days
per month for the treatment of pain in more than 2 of the past 3 months.
[28] History of drug or alcohol abuse/dependence within 1 year prior to Visit 1 
(excessive or compulsive use as judged by the investigator), or currently using 
drugs of abuse (including opioids, barbiturates, and marijuana), or any 
prescribed or over-the-counter medication in a manner that the investigator 
considers indicative of abuse/dependence.
[29] Have a positive urine drug screen for any substances of abuse at Visit 1.  
Note: A retest is allowed if the urine drug screen is positive for any 
prescribed substance or if, in the judgment of the investigator, there is an 
acceptable medical explanation for the positive result.  The results of the retest 
must be negative at or prior to Visit 2.

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[30] Have an acute, serious, or unstable medical condition that, in the judgment of 
the investigator, indicates a medical problem that would preclude study 
participation. 
Other Exclusions
[31] In the opinion of the investigator, have other issues which would interfere 
with compliance with the study requirements and completion of evaluations 
required for this study.
[32] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[33] Are Lilly employees.
[34] Are unwilling or unable to comply with the use of a data collection device.
6.3.
Lifestyle Restrictions
No changes in lifestyle or dietary requirements are required during the study. Fasting is not 
required prior to collection of laboratory samples.
Study participants should be instructed not to donate blood or blood products during the study or 
for 5 months following the last administration of investigational product.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be
considered for rescreen once, with approval from Lilly Medical for only the criteria shown 
below.  If rescreening is performed, the individual must sign a new ICF and will be assigned a 
new identification number

Inclusion Criterion [1] (age):  If patients are less than age 18 at time of informed 
consent, they may be rescreened if they reach age 18 during the study enrollment 
period.

Inclusion Criterion [4] (2 to 4 previous treatment failures)

Inclusion Criterion [9] (negative pregnancy test)

Exclusion Criterion [13] (washout previous investigational product)

Exclusion Criterion [16] (washout previous preventives)

Exclusion Criterion [26] (pregnant or nursing)
Patients using a concomitant medication that requires a stable dose for a specific duration prior 
to Visit 2 may be rescreened if additional time is needed to meet the duration requirement.
In addition, after consultation with and approval by a Lilly Medical representative, a patient may 
be rescreened if there is an unexpected technical difficulty with the electronic diary capture 
during the prospective baseline period.

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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of galcanezumab 120 mg (with an initial 240-mg loading dose)
administered by subcutaneous injection once monthly with placebo.  Site staff will administer
injections of galcanezumab or placebo at 3 office visits during the double-blind treatment phase 
and administer galcanezumab at 3 office visits during the open-label treatment phase (Section 2).  
Possible injection sites include the abdomen, thigh, and upper arm.  Buttocks may also be used, 
if needed.  Site staff are encouraged to administer comfort measures (such as cold compress, ice 
pack, or topical anesthetic cream) to the injection site prior to or after the injection at their 
clinical discretion or as needed. Injection locations and any comfort measures used will be 
recorded in the patient’s electronic case report form (eCRF).
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing 

at the end of the study returning all unused medication to Lilly, or its designee, 
unless the sponsor and sites have agreed all unused medication is to be destroyed 
by the site, as allowed by local law
7.1.1. Packaging and Labelling
Galcanezumab and matching placebo (excipients only) will be supplied as an injectable solution 
in 1-mL, single-dose, prefilled, disposable manual syringes with study-specific labels during the 
double-blind treatment phase. Each syringe of galcanezumab is designed to deliver 
galcanezumab 120 mg. The syringes (and contents) containing either galcanezumab or placebo 
will be visibly indistinguishable from each other. Syringes will be supplied in single syringe
cartons, with the appropriate quantity of syringes dispensed specific to the planned dispensing 
schedule of the investigational product.
Clinical study materials will be labeled according to the country’s regulatory requirements.
7.1.2. Medical Devices
The manufactured medical devices provided for use in the study are prefilled syringes.
7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at
Visit 3.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).  The IWRS will be used to assign
double-blind investigational product to each patient during the double-blind treatment phase.  
The IWRS will also be used to assign investigational product during the open-label treatment 

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phase. Site personnel will confirm that they have located the correctly assigned package by 
entering the confirmation number found on the package into the IWRS.
To achieve between-group comparability, the randomization will be stratified by country and
migraine frequency from the prospective baseline period (low frequency episodic, high 
frequency episodic, chronic).  Low frequency episodic will be defined as 4 to <8 migraine 
headache days per 30-day period.  High frequency episodic will be defined as 8 to 14 migraine 
headache days per 30-day period, with <15 headache days (migraine or nonmigraine) per 30-day 
period.  Chronic migraine will be defined as ≥8 migraine headache days per 30-day period, with 
≥15 headache days (migraine or nonmigraine) per 30-day period. To ensure an appropriate 
balance of patients with episodic and chronic migraine, the sponsor will stop enrollment of 
patients with chronic migraine if the number of patients exceeds approximately 40%.  
7.2.1. Selection and Timing of Doses
This is a fixed-dose study.  The actual time of all dose administrations will be recorded in the 
patient’s eCRF. Investigational product injections are to be administered after all other study 
procedures are completed for the given visit.
7.3.
Blinding
This is a double-blind study.  Blinded crossover to an open-label treatment phase is included in 
this study.
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete.  After the reporting 
database is locked for statistical analysis of the double-blind treatment phase, a limited number 
of sponsor personnel will be unblinded to complete the study report and prepare for submission.  
However, any sponsor personnel continuing with the management and oversight of the trial will 
remain blinded to patients’ previous treatment assignment.
Emergency unblinding for AEs may be performed through the IWRS.  This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment.  All 
unblinding events are recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient
must be discontinued from the study.  In cases where there are ethical reasons to have the patient 
remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician or clinical research scientist for the patient to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  Patient
safety must always be the first consideration in making such a determination.  If a patient’s 
treatment assignment is unblinded, Lilly must be notified immediately.  If the investigator 
decides that unblinding is warranted, it is the responsibility of the investigator to promptly 
document the decision and rationale and notify Lilly as soon as possible.

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7.4.
Dosage Modification
No dose modification will be allowed during the double-blind or open-label treatment phases.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

the investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation, and final disposition records).
The packaged investigational product must be stored according to the storage requirements 
printed onto the packaging label.
To administer the galcanezumab injections, the investigational sites are to refer to the pharmacy
binder for the preparation and handling instructions of the packaged investigational product.
7.6.
Treatment Compliance
Investigators will be required to document the administration of investigational product in the 
eCRF.
Investigational product must be administered as indicated in the Schedule of Activities 
(Section 2).  If the investigator is unable to administer the investigational product in the allowed 
window, the situation should be discussed with Lilly to determine if the patient may continue.  
7.7.
Concomitant Therapy
Table CGAW.4 contains the list of medications that are, and are not, allowed in this study.  Any 
changes in the list of allowed/not allowed medications will be communicated to investigators and 
will not constitute a protocol amendment.  The concomitant use of acute medications to treat 
migraine is allowed, with some limitations.  Treatments used for the prevention of migraine, 
including nutraceuticals and non-pharmacological interventions, are not allowed at any time 
during Study Periods II, III, or IV.  Patients should have washed out all migraine preventive 
treatments at least 5 days prior to Visit 2.  Botulinum toxin A or B in the head or neck area for 
therapeutic use is not allowed within 3 months prior to Visit 2.  Nerve blocks or use of 
therapeutic devices (such as transcranial magnetic stimulation) in the head or neck area or for 
migraine prevention are not allowed within 30 days before Visit 2.  

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Patients will capture whether they took any acute headache medication as part of their daily diary 
entry during Study Periods II, III, and IV.  Acute headache medication name, dose, and date will 
be recorded by patients during Study Periods II, III, and IV on a headache medication log, which 
will be returned to site staff at each study visit.  
Table CGAW.4.
Treatments Allowed and Treatments Not Allowed as Concomitant 
Therapy
A.  Medications allowed for the ACUTE treatment of migraine headaches or other pain 
or injury:
Acetaminophen (paracetamol), NSAIDs; Triptans; Ergotamine and derivatives; Isometheptene mucate, 
dichloralphenazone and acetaminophen combination (Midrin); or combinations thereof.
The following medications are allowed with restrictions:
1.Opioid and barbiturates no more than 4 days/month.
2.Single dose of injectable steroids allowed only once during the study, in an emergency setting (SP II, III, IV).
B.  Medications, Procedures or Devices not allowed for any reason/indication in SP II, 
III, or IV:
Acetazolamide
Acupuncture
Anticonvulsants/Antiepileptics
Antipsychotics 
Beta-blockers 
Botulinum toxin applied to head/neck area for therapeutic use 
Cannabis / Cannabinoids
Chiropractic procedures, physiotherapy, TENS or other electric devices on head and neck
Corticosteroids for oral use
Flunarizine
Gabapentin
Herbals with anti-inflammatory effect (feverfew, willow bark, petasites/butterbur)
Iprazochrome
Lomerizine
Monoamine oxidase inhibitors (MAOIs)
Memantine
Methysergide
Neurotropin®
Nerve block in head/neck area
Oxetorone
Pizotifen
Pregabalin
Serotonin 5HT2a/2c antagonists, e.g.:  trazodone, nefazodone  
Stimulants (prescription strength), e.g.:  methylphenidate, dextroamphetamine, mixed amphetamine salts
Tizanidine
Tricyclic antidepressants (TCAs)
Triptans for prophylaxis of menstrual related migraine 
Venlafaxine
Verapamil

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Treatments Allowed and Treatments Not Allowed as Concomitant Therapy
C.  Restricted medication during SP II and III:  Use of the following medications for 
indications other than migraine prevention is allowed providing the dose is stable 
2 months prior to Visit 2 and is expected to remain stable during Visit 2 through 6. 
ACE inhibitors 
Angiotensin receptor blockers (ARBs)
Benzodiazepines
Bupropion 
Calcium-channel blockers (except verapamil, flunarizine, and lomerizine)
Clonidine 
Guanfacine 
Mirtazapine 
SSRIs/NRIs/SNRIs (other than venlafaxine) 
Use of electric devices (ie, TENS), physiotherapy, chiropractic procedures on low back and extremities
D.  During SP IV (Visit 6 through 9):
No medications from List B.
No medications or treatments for the prevention of migraine.
Medications in List C may now be started, stopped, or have dose modification as long as not being used for 
migraine prevention.
Abbreviations:  5HT = 5-hydroxytryptamine; ACE = angiotensin-converting enzyme; NRI = norepinephrine 
reuptake inhibitor; NSAID = nonsteroidal anti-inflammatory drug; SNRI = serotonin-norepinephrine reuptake 
inhibitor; SP = Study Period; SSRI = selective serotonin reuptake inhibitor; TENS = transcutaneous electrical 
nerve stimulation.
7.8.
Treatment after the End of the Study
Investigational product will not be made available to patients after conclusion of the study.

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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets one of the following conditions after consultation with 
Lilly Medical:  

ALT or aspartate aminotransferase (AST) >8X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and TBL >2X ULN or international normalized ratio >1.5

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)

ALP >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%)
Patients who are discontinued from investigational product due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via eCRF.
Patients must be discontinued from investigational product in the event of pregnancy.
Patients must be discontinued from investigational product if the patient requests to discontinue.
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up/early termination procedures per Section 2 (Schedule of 
Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of this protocol.
8.1.2. Temporary Discontinuation from Study Treatment
Not applicable.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and Lilly Medical agree it is medically appropriate to 
continue, the investigator must obtain documented approval from Lilly Medical to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product. Safety follow up/early termination procedures are as outlined in 
Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the 
protocol.

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8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

Enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

Investigator Decision
o
the investigator decides that the patient should be discontinued from the 
study
o
if the patient, for any reason, requires treatment with a disallowed 
therapeutic agent that has been demonstrated to be effective for the study 
indication (prevention of migraine) during Study Periods II, III, or IV, 
discontinuation from the study occurs prior to introduction of the new 
agent

Patient Decision
o
the patient requests to be withdrawn from the study
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up/early termination procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.

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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
ePRO Diary:  Patients will be asked to use an ePRO device to record headache information, 
including reporting headaches, intensity of headache, headache features, and whether any acute 
headache medication was taken. The system also will be used to collect information about
migraine-associated symptoms (eg, photophobia, phonophobia, nausea, and/or vomiting).
9.1.2. Secondary Efficacy Assessments
Secondary efficacy assessments in this study (Table CGAW.2) are intended to facilitate the 
collection and analysis of information such as response (≥50% reduction from baseline in the 
number of migraine headache days per month) and changes in medication use for the acute 
treatment of headache.  Much of this information will be provided by the ePRO diary; however, 
details of acute headache medication use will be captured by a headache medication log and 
reported at monthly site visits.  The scale to be used for secondary efficacy assessment is 
summarized below. 
Patient Global Impression of Severity Scale:  The Patient Global Impression of Severity 
(PGI-S) scale (Guy 1976) is a patient-rated instrument that measures illness severity.  For this 
study, the patient will be instructed as follows: “Considering migraine as a chronic condition, 
how would you rate your level of illness?”  The PGI-S includes a range of possible responses, 
from 1 (“normal, not at all ill”) to 7 (“extremely ill”). 
9.1.3. Appropriateness of Assessments
The efficacy and safety assessments used in this study have been well documented and are 
generally regarded as reliable, accurate, and relevant in this patient population.  This includes 
health outcomes measures considered to be appropriate for evaluating changes in quality of life, 
global functioning, disability, 
.
CCI

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9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report and ECG.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.  However, any worsening of the primary study condition should be 
recorded as an AE.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s pre-existing conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record via eCRF any change 
in the condition(s) and any new conditions as AEs. Investigators should record their assessment 
of the potential relatedness of each AE to protocol procedure or investigational product via 
eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, and pathologies.  
A “reasonable possibility” means that there potentially is a cause and effect relationship between 
the investigational product, study device, and/or study procedure and the AE.
The investigator will answer yes or no when making this assessment.
The investigator will use AE follow-up forms to record additional details regarding AEs related 
to injection sites and hypersensitivity events.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible the circumstances leading 
to discontinuation of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

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
death

initial or prolonged inpatient hospitalization

a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.

when a condition related to the investigational device (eg, prefilled syringe) 
necessitates medical or surgical intervention to preclude either permanent 
impairment of a body function or permanent damage to a body structure, the 
serious outcome of “required intervention” will be assigned.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received investigational product.  However, if an SAE occurs after signing the ICF, but prior to 
receiving investigational product, the SAE should be reported to the sponsor as per SAE 
reporting requirements and timelines (see Section 9.2) if it is considered reasonably possibly 
related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  Patients with a serious hepatic AE should have additional data collected using the 
eCRF. 
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements, any pregnancy that occurs 
during the study, including those in which conception occurred within 5 months after last 
administration of investigational product, should be reported following the SAE process to 
collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in patients once they have 
discontinued and/or completed the study (the patient disposition eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a patient has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study treatment or study participation, the investigator must promptly notify Lilly.

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9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the 
identification, recording, and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product (or drug delivery system such as a 
prefilled syringe) so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB.  
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities (Section 2).  Electrocardiograms should be collected prior to blood draws and dosing.  
Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.  Electrocardiograms will have a central overread and 
should be recorded according to the study-specific recommendations included in the ECG 
manual.  
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
patient receives the first dose of the investigational treatment should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.2. Vital Signs
Vital signs will include body temperature, blood pressure, and pulse.  Blood pressure and pulse 
will be measured as a single measurement in the sitting position prior to blood draws and dosing,
according to the Schedule of Activities (Section 2) and following the study-specific 
recommendations included in the Manual of Operations for the study.  
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via eCRF.

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9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2). 
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
In addition, an immunogenicity blood sample will be collected, when possible, for any patient 
who experiences a serious potential systemic hypersensitivity event during the study as judged 
by the investigator.  This immunogenicity blood sample should be collected immediately or as 
soon as possible, taking into consideration the availability and well-being of the patient. Exact 
date and time of the sample should be recorded on the laboratory requisition form.  
Lilly or its designee will provide the investigator with the results of laboratory tests analyzed by 
a central vendor.  Note that any anti-drug antibody result that may unblind a site would not be
shared.
9.4.4. Immunogenicity Assessments
Immunogenicity will not be proactively evaluated in this study.  However, where local 
regulations and ERBs allow, a single venous blood sample will be collected prior to the start of 
treatment as specified in the Schedule of Activities (Section 2) and stored for future 
immunogenicity assessments, if applicable.  Immunogenicity samples may also be collected 
from a patient in the event of a serious potential systemic hypersensitivity event, as noted in 
Section 9.4.3.  
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and ERBs allow, at a facility selected by the sponsor.  
The duration allows the sponsor to respond to future regulatory requests related to 
galcanezumab.  Any samples remaining after 15 years will be destroyed.
9.4.5. Safety Monitoring
Investigators are responsible for monitoring individual patient safety throughout the trial.
Neurological examinations will be conducted in order to assess for any signs of pre-existing or 
treatment-emergent neurological abnormalities such as stroke or other cerebrovascular events.
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
blinded methods.
9.4.5.1.
Hepatic Safety Monitoring
If a study patient experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X
ULN, liver testing (Appendix 4) should be repeated within 3 to 5 days including ALT, AST, 
ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm the 
abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 

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consultation with Lilly Medical. Monitoring of ALT, AST, TBL, and ALP should continue until 
levels normalize or return to approximate baseline levels.
Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if one or more of the following 
conditions occur: 

elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests

elevated serum TBL to ≥ 2X ULN (except for cases of known Gilbert’s 
syndrome)

elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests

patient discontinued from treatment due to a hepatic event or abnormality of 
liver tests

hepatic event considered to be an SAE
9.5.
Pharmacokinetics
Not applicable. 
9.6.
Pharmacodynamics
Not applicable. 
9.7.
Genetics
9.7.1. Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations and ERBs allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to galcanezumab and 
to investigate genetic variants thought to play a role in migraine.  Assessment of variable 
response may include evaluation of AEs or differences in efficacy.  These studies may include,
but are not limited to, CGRP and molecules that directly and indirectly influence CGRP 
signaling to evaluate their association with observed response to galcanezumab.  
All pharmacogenetic samples will be coded with the patient number.  These samples and any 
data generated can be linked back to the patient only by the investigator site personnel.  Samples 
will be destroyed according to a process consistent with local regulations.  
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if local regulations and/or ERBs impose shorter time limits, at a facility 
selected by the sponsor.  This retention period enables use of new technologies, response to 
regulatory questions, and investigation of variable response that may not be observed until later 
in drug development or when the drug becomes commercially available.

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Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome wide association studies, candidate gene studies, and epigenetic analyses.  
Regardless of technology utilized, genotyping data generated will be used only for the specific 
research scope described in this section. 
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of patient response (including 
safety), and clinical outcome.  Sample collection is incorporated into clinical studies to enable 
examination of these questions through measurement of biomolecules including
deoxyribonucleic acid (DNA), ribonucleic acid (RNA), proteins, lipids, and other cellular 
elements.
Blood samples for nonpharmacogenetic biomarker research will be collected at the times
specified in the Schedule of Activities (Section 2) where local regulations and ERBs allow.
Samples will be used for research on the drug target, disease process, variable response to 
galcanezumab, pathways associated with migraine and/or other pain conditions, mechanism of 
action of galcanezumab, and/or research method or in validating diagnostic tools or assay(s) 
related to migraine and/or other pain conditions.  
All biomarker samples will be coded with the patient number.  These samples and any data 
generated can be linked back to the patient only by the investigator site personnel.  Samples will 
be destroyed according to a process consistent with local regulations.  
Samples will be retained for a maximum 15 years after the last patient visit for the study, or for a 
shorter period if local regulations and ERBs impose shorter time limits, at a facility selected by 
the sponsor.  This retention period enables use of new technologies, response to regulatory 
questions, and investigation of variable response that may not be observed until later in drug 
development or when the drug is commercially available.
9.9.
Health Economics
Health outcome measures of galcanezumab in patients with migraine will be collected as 
described in the Schedule of Activities (Section 2) based on the following scales:
Migraine-Specific Quality of Life Questionnaire version 2.1:  The Migraine-Specific Quality 
of Life Questionnaire version 2.1 (MSQ v2.1) is a self-administered health status instrument that 
was developed to address the physical and emotional impact on functioning that is of specific 
concern to individuals suffering from migraine headaches. The instrument consists of 14 items 
that address 3 domains: (1) Role Function-Restrictive; (2) Role Function-Preventive; and (3) 
Emotional Function (Jhingran et al. 1998b).  The restrictive domain specifically measures 
disability as related to the impact on performance of normal activities, with the preventive 
domain addressing complete functional impairment and the emotional domain assessing the 
feelings related to disabling monthly migraine headache days. Responses are given using a 

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6-point Likert-type scale, ranging from “none of the time” to “all of the time.”  Raw scores for 
each domain are computed as a sum of item responses, with the collective sum providing a total 
raw score that is then converted to a 0 to 100 scale, with higher scores indicating a better health
status, and a positive change in scores reflecting functional improvement (Jhingran et al. 1998a; 
Martin et al. 2000).  The instrument was designed with a 4-week recall period and is considered 
reliable, valid, and sensitive to change in functional impairment due to migraine (Jhingran et al. 
1998b; Bagley et al. 2012).
Migraine Disability Assessment:  The Migraine Disability Assessment (MIDAS) is a patient-
rated scale which was designed to quantify headache-related disability over a 3-month period.  
This instrument consists of 5 items that reflect the number of days reported as missed, or with 
reduced productivity at work or home and social events.  Each question is answered as the 
number of days during the past 3 months of assessment, ranging from 0 to 90, with the total 
score being the summation of the 5 numeric responses.  A higher value is indicative of more 
disability (Stewart et al. 1999, 2001).  This instrument is considered highly reliable and valid,
and is correlated with clinical judgment regarding the need for medical care (Stewart et al. 1999,
2001). For clinical interpretability, 4 categorical grades were developed based on the total score:
Grade I (0 to 5) is for little or no disability, Grade II (6 to 10) is for mild disability, Grade III 
(11 to 20) is for moderate disability, and Grade IV (21+) is for severe disability.  The severe 
disability category has subsequently been subdivided into Grade IV-A (severe [21 to 40]) and 
Grade IV-B (very severe [41 to 270]) because a high proportion of patients with chronic 
migraine are in Grade IV (Blumenfeld et al. 2011).
Health Care Resource Utilization and Employment Status:  The Health Care Resource 
Utilization questionnaire (HCRU) will be solicited by study personnel while documenting patient 
responses. The HCRU consists of 3 questions, asking about the number of hospital emergency
room visits, overnight stays in a hospital, and any other visits with a healthcare professional that 
occurred since the patient’s last study visit, outside of visits associated with their participation in 
the clinical trial.  Patients are also specifically asked about the number of healthcare events that 
are related to migraine headaches.  The baseline visit will include the same questions, however 
with the frame of reference being over the last 6 months.  A question on employment status will 
also be solicited, given the correlation and potential confounding with health outcomes measures.
Migraine Interictal Burden Scale:  The 4-item Migraine Interictal Burden Scale (MIBS-4) 
measures the burden related to headache in the time between attacks. The self-administered 
instrument consists of 4 items that address disruption at work and school, diminished family and 
social life, difficulty planning, and emotional difficulty.  The questionnaire specifically asks 
about the effect of the disease over the past 4 weeks on days without a headache attack.  
Response options include: don’t know/not applicable, never, rarely, some of the time, much of 
the time, or most or all of the time. Each response has an associated numerical score, with the 
summation across all 4 items resulting in a total score ranging from 0 to 12, and the level of 
interictal burden being categorized into the following: 0 for none, 1-2 mild, 3-4 moderate, and 
>5 severe (Buse et al. 2007, 2009).  

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European Quality of Life 5-Dimensions 5-Levels:  The European Quality of Life 
5-Dimensions 5-Levels (EQ-5D-5L) questionnaire is a widely used, generic patient-rated scale
that assesses current health status at the time of questionnaire completion, that is ‘today’
(EuroQol 1990; Herdman et al. 2011). The questionnaire consists of 2 parts. The first part 
assesses 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) that have 5 possible levels of response (no problems, slight problems, 
moderate problems, severe problems, extreme problems). This part of the EQ-5D-5L can be 
used to generate a health state index score, which is often used to compute quality-adjusted life 
years for utilization in health economic analyses.  The health state index score is calculated based 
on the responses to the 5 dimensions, providing a single value on a scale from less than 0 (where 
zero is a health state equivalent to death; negative values are valued as worse than dead) to 
1 (perfect health), with higher scores indicating better health utility. The second part of the 
questionnaire consists of a visual analog scale (VAS) on which the patient rates their perceived 
health state from 0 (the worst health you can imagine) to 100 (the best health you can imagine). 
Work Productivity and Activity Impairment Questionnaire: The Work Productivity and 
Activity Impairment Questionnaire (WPAI) is a patient-reported instrument developed to 
measure the impact on work productivity and regular activities attributable to a specific health 
problem (Reilly et al. 1993); for this study, the questions are specific to migraine.  Recall period 
is the past 7 days.  The scale contains 6 items that measure: 1) employment status, 2) hours 
missed from work due to the specific health problem, 3) hours missed from work for other 
reasons, 4) hours actually worked, 5) degree health affected productivity while working, and 6) 
degree health affected productivity in regular unpaid activities. Four scores are calculated from 
the responses to these 6 items: absenteeism, presenteeism, work productivity loss, and activity 
impairment. Scores are calculated as impairment percentages, with higher numbers indicating 
greater impairment and less productivity, ie, worse outcomes.
 
 
 
 
 
 
 
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10. Statistical Considerations
10.1. Sample Size Determination
The study will enroll approximately 420 patients. Eligible patients will be randomized in 
blinded fashion in a 1:1 ratio to placebo or galcanezumab 120 mg (with a loading dose of 
240 mg).  With the assumption of a 10% discontinuation rate and an effect size of 0.39, it is 
estimated that this sample size will provide approximately 96% power that galcanezumab will 
separate from placebo at a 2-sided significance level of 0.05 for the intent-to-treat (ITT)
population in this study.
The study is also powered for the subpopulation of patients with episodic migraine. The study 
will seek to enroll approximately 250 patients with episodic migraine as determined during the 
prospective baseline period. With the assumption of a 10% discontinuation rate and an effect 
size of 0.46, it is estimated that this will provide approximately 93% power that galcanezumab 
will separate from placebo at a 2-sided significance level of 0.05 for the episodic migraine 
subpopulation in this study.  
Assumptions in this sample size calculation were based on data from 3 double-blind, placebo-
controlled, Phase 3 studies, with an adjustment made to reflect differences in this study and the 
potential impact of the development phase and the inclusion of an open-label treatment phase on 
placebo responses.  
10.2. Populations for Analyses
Three analysis populations are defined as follows: ITT population, safety population, and open-
label treatment population. The ITT and safety populations include all patients who are 
randomized and receive at least one dose of investigational product. The open-label treatment 
population includes all patients who enter the open-label treatment phase as indicated by 
receiving any injection starting from Visit 6.
Unless otherwise stated, all efficacy analyses will be analyzed according to the ITT principle on 
the ITT population; that is, patients will be analyzed according to the treatment to which they 
were randomized, regardless of whether they actually received a different treatment. Safety 
analyses will be conducted on the safety population based on treatment the patient received.  
Analyses for the open-label treatment phase only will be based on the open-label treatment 
population.
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. Details of 
statistical analysis methods will be described in the statistical analysis plan (SAP). 
Unless otherwise specified, analyses will be conducted on the ITT population for efficacy 
analyses and on the safety population for safety analyses (see Section 10.2).  When change from 

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baseline is assessed, the patient will be included in the analysis only if he/she has a baseline and 
a postbaseline measurement.
Continuous efficacy variables with repeated measures will be analyzed using mixed model 
repeated measures (MMRM) methods. The MMRM will include the fixed categorical effects of 
treatment, baseline migraine headache day frequency category (low episodic migraine, high 
episodic migraine, chronic migraine), pooled country, month, and treatment-by-month 
interaction, as well as the continuous fixed covariates of baseline and baseline-by-month 
interaction. For the model of the primary endpoint, the baseline migraine headache day 
frequency category will be excluded from the covariates since the continuous baseline monthly 
migraine headache day value is already in the model.  
For continuous efficacy variables without repeated measures, an analysis of covariance 
(ANCOVA) model with last observation carried forward (LOCF) imputation will be used, which 
contains the main effects of treatment, baseline migraine headache day frequency category, and 
pooled country, as well as the continuous fixed covariate of baseline. Type III sum-of-squares 
for the Least Squares Means (LSMeans) will be used for the statistical comparisons.
Binary efficacy variables with repeated measures will be analyzed using a generalized linear 
mixed model (GLIMMIX) as pseudo-likelihood-based mixed effects repeated measures analysis.  
The GLIMMIX model will include the fixed, categorical effects of treatment, month, and 
treatment-by-month interaction, as well as the continuous, fixed covariate of baseline value.
For binary efficacy variables without repeated measures, comparisons between treatment groups 
will be performed using logistic regressions with the same model terms as the ANCOVA model. 
Pooled country may be removed to ensure model convergence.  
For continuous safety variables with repeated measures, MMRM methods will be used, as well 
as an ANCOVA model with LOCF imputation if deemed appropriate.  When an ANCOVA 
model is used for safety measures, the model will contain the main effect of treatment, as well as
the continuous fixed covariate of baseline. Type III sum-of-squares for the LSMeans will be 
used for the statistical comparisons.
For categorical safety variables (such as AEs and other categorical changes of interest), as well 
as categorical baseline characteristics, comparisons between treatment groups will be performed 
using Fisher’s exact test.
Treatment effects will be evaluated based on a 2-sided significance level of 0.05 for all the 
efficacy and safety analyses unless otherwise stated. The 95% confidence intervals for the 
difference in LSMeans between treatment groups will be presented.  Type I error due to multiple 
comparisons for the primary and key secondary objectives will be controlled using sequential 
gating procedure (see Section 10.3.3.2). There will be no adjustments for multiplicity for 
analyses of other data (other secondary objectives or tertiary objectives).
Unless otherwise noted, all efficacy and safety analyses will be conducted on the total population
and the episodic migraine subpopulation.  

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Countries will be pooled as deemed necessary for statistical analysis purposes.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any change to the data analysis methods 
described in the protocol, and the justification for making the change, will be described in the 
clinical study report or SAP.  Additional exploratory analyses of the data will be conducted as 
deemed appropriate.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
The number and percentage of ITT patients who complete the study or discontinue early will be 
tabulated for all treatment groups for Study Period III and Study Period IV separately. Reasons 
for discontinuation will be compared between treatment groups for Study Period III with the ITT 
population. Descriptive statistics only will be presented for the treatment groups in Study 
Period IV.  In addition, subcategories of discontinuation due to patient decision will be 
summarized.
Patient allocation by investigator will be summarized for Study Period III for all ITT patients.  
Patient allocation by investigator will also be listed for all study periods.
10.3.2.2. Patient Characteristics
The following patient characteristics at baseline will be summarized by treatment group for all 
ITT patients.

Demographic (age, sex, ethnic origin, height, weight, body mass index)

Migraine and/or headache-related measures from the ePRO diary per 30-day 
baseline period

Number of prior migraine preventive treatment failures from the list in Section 6.1
(Inclusion Criterion [4]):
o
Failed 2 medication categories
o
Failed 3 medication categories
o
Failed 4 medication categories

Alcohol, tobacco, caffeine, and nicotine consumption

Medical history and pre-existing conditions
Medical history and pre-existing conditions will be summarized by preferred term within system 
organ class (SOC).
10.3.2.3. Concomitant Therapy
The proportion of patients who received concomitant medication collected from eCRFs and the 
acute medications collected on the headache medication log will be summarized for all ITT 
patients for Study Period III and Study Period IV separately.

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10.3.2.4. Treatment Compliance
Dosing will occur at monthly study visits.  Treatment compliance for each patient in the double-
blind treatment phase will be calculated as the number of completed scheduled dosing visits in 
which the patient receives an injection, divided by the number of completed scheduled dosing 
visits, including any skipped dosing visits before the last dosing visit (Visit 5) or early 
discontinuation visit in the double-blind treatment phase.
10.3.2.5. Electronic Patient-reported Outcome Diary Compliance
Electronic patient-reported outcomes diary compliance at each 1-month period (including 
baseline, Month 1, Month 2, Month 3, … to Month 6) as well as for Study Period III overall 
(Month 1 through Month 3) will be calculated.  Diary compliance at each period is calculated as:
Actual number of diary days in the period
Expected number of diary days in the period100
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary efficacy endpoint is the overall mean change from the baseline period in the number 
of monthly migraine headache days during the 3-month double-blind treatment phase, and the 
primary analysis will evaluate the efficacy of galcanezumab compared with placebo in the total 
ITT population.  
The primary analysis will be performed using a restricted maximum likelihood-based MMRM
technique.  The analysis will include the fixed categorical effects of treatment, pooled country, 
month, and treatment-by-month interaction, as well as the continuous fixed covariates of baseline 
number of migraine headache days and baseline number of migraine headache days-by-month 
interaction.
An unstructured covariance structure will be used to model within-patient errors.  The Kenward-
Roger (Kenward and Roger 1997) approximation will be used to estimate denominator degrees 
of freedom.  If the model does not converge with both the Hessian and the G matrix being 
positive definite under the default fitting algorithm used by PROC MIXED, the Fisher scoring 
algorithm will be implemented by specifying the SCORING option in SAS.  If the model still 
fails to converge, the model will be fit using covariance matrices of the following order specified 
by a decreasing number of covariance parameters until convergence is met:

Heterogeneous Toeplitz

Heterogeneous First-order autoregressive

Toeplitz

First-order autoregressive
When the unstructured covariance matrix is not utilized, the sandwich estimator (Diggle and 
Kenward 1994) will be used to estimate the standard errors of the fixed effects parameters.  The 
sandwich estimator is implemented by specifying the EMPIRICAL option in SAS®.  When the 

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sandwich estimator is utilized, the Kenward-Roger approximation for denominator degrees of 
freedom cannot be used.  Instead, the denominator degrees of freedom will be partitioned into 
between-subject and within-subject portions by the DDFM=BETWITHIN option in SAS®.  
SAS® PROC MIXED will be used to perform the analysis.
10.3.3.2. Key Secondary Analyses
The key secondary measures (see Table CGAW.2) will be analyzed for the double-blind 
treatment phase (Study Period III). The analysis models are described in Section 10.3.1. 
Populations tested will include the total population (episodic and chronic migraine combined) 
and the episodic migraine subpopulation. Patients will be categorized as episodic or chronic 
based on their number of migraine and headache days during the prospective baseline period.  
In order to control for type I error, the key secondary analyses will be tested using a gated testing 
approach at a 2-sided alpha level of 0.05. If the null hypothesis is rejected for the primary 
endpoint, key secondary endpoints will be sequentially tested following the gatekeeping 
hierarchy depicted in Figure CGAW.2, starting with the comparison of change in migraine 
headache days between treatment groups based on the episodic migraine subpopulation.  If the 
null hypothesis is rejected for that comparison, then the comparison of 50% response rate 
between treatment groups will be tested in the total population.  If that null hypothesis is 
rejected, then the next comparison in the sequence will be tested (50% response rate in the 
episodic subpopulation), following this same pattern until all hypotheses are tested or until the 
null hypothesis is accepted for an endpoint, at which point, any further testing would stop for the 
key secondary objectives.
If the multiple testing approach for key secondary measures needs to be changed, the updated 
approach will be provided in the SAP, and it should not lead to modification of this protocol.

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Abbreviations: CM = chronic migraine patients; EM = episodic migraine patients; 
MHD = the number of monthly migraine headache days (mean change from baseline); 
MSQ RR = Migraine Specific Quality of Life Questionnaire Role Function-Restrictive 
domain; response = response rate.
Note:  All testing will be conducted at a 2-sided alpha of 0.05.
Figure CGAW.2.
Gatekeeping sequence for testing of primary and key secondary 
endpoints.
10.3.3.3. Other Secondary and Tertiary Analyses
There will be no adjustments for multiplicity for analyses of the other secondary or tertiary 
endpoints not listed in Figure CGAW.2.  The analysis models are described in Section 10.3.1.
10.3.4. Safety Analyses
The safety and tolerability of treatment will be assessed by summarizing the following:

TEAEs

SAEs

AEs leading to discontinuation

potential hypersensitivity events

AEs related to injection sites

vital signs and weight

ECGs

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
laboratory measurements 
Unless specified otherwise, the categorical safety analyses will include both scheduled and 
unscheduled visits.  Comparisons between treatment groups for all categorical safety measures 
will be made using Fisher’s exact test for Study Period III with the safety population.  
Descriptive statistics only will be presented for the analyses in Study Period IV.
Analyses of continuous safety data will be conducted for Study Period III and Study 
Period III/IV using the safety population.  In those analyses, only values collected at scheduled 
visits will be used.
10.3.4.1. Treatment-Emergent Adverse Events
Treatment-emergent adverse events are defined as the reported AEs that first occurred or 
worsened during the postbaseline phase compared with the baseline phase.  For each TEAE, the 
reported severity level of the event (mild, moderate, or severe) will be determined by patient or 
physician opinion.  The Medical Dictionary for Regulatory Activities (MedDRA) Lowest Level 
Term (LLT) will be used in the treatment-emergent computation.  For each LLT, the maximum 
severity at baseline will be used as the baseline severity.  If the maximum severity during 
postbaseline is greater than the maximum baseline severity, the event is considered to be 
treatment-emergent for the specific postbaseline period.  Safety analyses for each study period
will use all visits up through the last scheduled visit in the prior study period as baseline.  For 
each patient and TEAE, the maximum severity for the MedDRA level being displayed (preferred 
term, High Level Term, or SOC) is the maximum postbaseline severity observed from all 
associated LLTs mapping to that MedDRA level.  
For events that are sex-specific, the denominator and computation of the percentage will include 
only patients from the specific sex.
10.3.4.2. Vital Signs
Vital signs collected during the study include systolic and diastolic blood pressure, pulse, and 
temperature. Blood pressure and pulse measurements will be taken when the patient is in a 
sitting position. 
The number and percentage of patients meeting criteria for treatment-emergent abnormalities in 
vital signs and weight at any time during study will be summarized.  Treatment group 
comparisons will be performed using Fisher’s exact test.
10.3.4.3. Electrocardiogram Intervals and Heart Rate
The corrected QT interval will be calculated using the Fridericia method (QTcF). The number 
and percentage of patients meeting criteria for treatment-emergent abnormalities in ECG 
intervals (pulse, QRS, and QTcF) and heart rate at any time during study will be summarized.  
Treatment group comparisons will be performed using the Fisher’s exact test.
10.3.4.4. Laboratory Tests
The incidence rates of patients with treatment-emergent abnormal, high, or low laboratory values 
at any time postbaseline will be assessed using Fisher’s exact test for each laboratory test.

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Patients will be defined as having a treatment-emergent low value if they have all normal or high 
values at baseline, followed by a value below the lower reference limit at any postbaseline visit.  
Patients with all normal or high values at baseline (no low values) will be included in the 
analysis of treatment-emergent low laboratory values. Patients will be defined as having a 
treatment-emergent high value if they have all normal or low values at baseline, followed by a 
value above the upper reference limit at any postbaseline visit.  Patients with all normal or low 
values at baseline (no high values) will be included in the analysis of treatment-emergent high 
laboratory values.
For analytes simply classified as normal or abnormal, patients will be defined as having a 
treatment-emergent abnormal value if they have all normal values at baseline, followed by an 
abnormal value at any postbaseline visit.  Patients with all normal values at baseline will be 
included in the analysis of treatment-emergent abnormal laboratory values.
10.3.5. Health Economics
The change from baseline for the double-blind treatment phase and for the open-label treatment 
phase for MSQ v2.1 (Role Function-Restrictive, Role Function-Preventive, and Emotional 
Function domains and total score), MIDAS (item scores and total score), EQ-5D-5L, MIBS-4, 
WPAI questionnaire, 
will be analyzed. In addition, categorical analyses will 
be performed. Changes in health care resource utilization and employment status will also be 
evaluated.  Details are summarized in the SAP.
10.3.6. Subgroup Analyses
Subgroup analyses for the primary efficacy measure of change from baseline in the number of 
monthly migraine headache days will include the following subgroup variables:

sex 

racial origin

age

migraine headache day frequency categories (high frequency episodic migraine, low 
frequency episodic migraine, or chronic migraine)

number of failed preventive migraine medication categories (2, 3, or 4)

geographical region 
Additional details are available in the SAP.
10.3.7. Interim Analyses
An interim analysis will be conducted after all patients have had the opportunity to complete 
Study Period III, and thus will be the final analysis of the primary efficacy endpoint.
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Study sites, patients, and all Lilly personnel directly involved in the continuing trial will remain 
blinded to patients’ double-blind treatment assignment.  Unblinding details are specified in the 
unblinding plan section of the SAP or a separate unblinding plan document.
No other interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director or designee will be consulted to determine 
whether it is necessary to amend the protocol.

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Headache. 2000;40(3):204-215.
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Messali A, Sanderson JC, Blumenfeld AM, Goadsby PJ, Buse DC, Varon SF, Stokes M, Lipton
RB. Direct and indirect costs of chronic and episodic migraine in the United States: a web-
based survey. Headache. 2016;56(2):306-322.
Pike J, Mutebi A, Shah N, Jackson J, Cotton S, Desai PR, Sapra S. Factors associated with a
history of failure and switching migraine prophylaxis treatment: an analysis of clinical practice
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12.
Appendices

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibodies
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the patients are 
aware of the treatment received.
CGRP
calcitonin gene-related peptide
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.

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enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ePRO
electronic patient-reported outcomes
EQ-5D-5L
European Quality of Life 5-Dimensions 5-Levels
ERB
ethical review board
 
GCP
good clinical practice
HCRU
Health Care Resource Utilization questionnaire
IB
Investigator’s Brochure
ICF
informed consent form
ICHD-3
International Classification of Headache Disorders – 3rd edition
IHS
International Headache Society
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
ITT
intent to treat:  The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a patient (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
patients allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.
IWRS
interactive web-response system
LOCF
last observation carried forward
LSMean
Least Squares Mean
MDD
major depressive disorder
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MIBS-4
4-item Migraine Interictal Burden Scale
MIDAS
Migraine Disability Assessment
MMRM
mixed model repeated measures
MSQ (v2.1)
Migraine-Specific Quality of Life Questionnaire version 2.1
PGI-S
Patient Global Impression of Severity
QTcF
Fridericia’s corrected QT interval
SAE
serious adverse event
SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study. 
SOC
system organ class
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin
TEAE
treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
ULN
upper limit of normal
VAS
visual analog scale
WPAI
Work Productivity and Activity Impairment Questionnaire
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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology
Clinical Chemistryc
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin (TBL)
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase (ALP)
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
HbA1c
Glucose
Albumin
Urinalysis
Total cholesterol
Specific gravity
Creatine kinase (CK)
pH
Protein
Pregnancy Test (females only)b
Glucose
Serum pregnancy or FSH
Ketones
Urine pregnancy test (local)
Blood
Urine leukocyte esterasea
Stored Samples
Urine drug screenb
Immunogenicityd
Pharmacogenetic sample (genetic sample/DNA)
RNA
Abbreviations:  DNA = deoxyribonucleic acid; FSH = follicle stimulating hormone; RBC = red blood cells; RNA = 
ribonucleic acid; WBC = white blood cells.
a
A positive urine leukocyte esterase result will require a follow-up sample with microscopic analysis and possibly 
a urine culture.
b
May be repeated during the study at the discretion of the investigator.
c
Fasting not required.
d
An immunogenicity sample may also be collected and analyzed in the event of a serious potential systemic 
hypersensitivity adverse event. Additional tests may be requested in order to further characterize the event 
and/or aid interpretation of the anti-drug antibody result.

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Appendix 3.
Study Governance Considerations

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Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential 
risks and benefits of participating in the study, and that their participation is 
voluntary.

ensuring that informed consent is given by each patient.  This includes 
obtaining the appropriate signatures and dates on the informed consent form 
(ICF) prior to the performance of any protocol procedures and prior to the 
administration of investigational product.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the study.

ensuring that a copy of the ICF is provided to the participant and is kept on 
file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF.
Appendix 3.1.2.
Recruitment
Eli Lilly and Company (Lilly) is responsible for the central recruitment strategy for patients.  
Individual investigators may have additional local requirements or processes.  
Appendix 3.1.3.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH) 
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative sites.  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative sites.  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator 
Brochure (IB) and updates during the course of the study

ICF

other relevant documents (for example, curricula vitae, advertisements)

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Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of 
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Investigators in this clinical trial should be neurologists, headache specialists, or other specialists 
with experience in headache clinical trials and treating migraine patients.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
An investigator selected by the study team will serve as the CSR coordinating investigator.  If 
this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the CSR coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the eCRFs, and 
study procedures.

make periodic visits to the study site

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
be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
In this study, patient headache data will be collected directly via an electronic patient-reported 
outcome (ePRO) diary as part of an ePRO/Clinical Outcome Assessment (COA) system. 
Patient-rated scales/questionnaires will be collected directly via an ePRO tablet device at each 
visit. Data entered into the ePRO/COA system will serve as the source data.
If ePRO records are stored at a third party site, investigator sites will have continuous access to 
the source documents during the study and will receive an archival copy at the end of the study 
for retention.
Any data for which the ePRO instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
Electronic case report form data will be encoded and stored in a clinical trial database.  Data 
managed by a central vendor, such as laboratory test data or ECG data, will be stored 
electronically in the central vendor’s database system.  Data will subsequently be transferred 
from the central vendor to the Lilly data warehouse.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient in this study will include a headache medication log on 
which patients will record their acute headache medication use during the study.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study I5Q-MC-CGAW is described in the Clinical Trial Agreement.

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Appendix 4.
Hepatic Monitoring Tests for Treatment-
Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, clinical 
research physician/clinical research scientist.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

Leo Document ID = 9bf46bdb-5aa8-4822-8250-caab66acac3e
Approver: 
Approval Date & Time: 22-Mar-2018 15:49:25 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 22-Mar-2018 15:49:25 GMT
Signature meaning: Approved
PPD
PPD