Clinical trial NCT02797951
Conditions: Episodic Cluster Headache Chronic Cluster Headache
Keywords: cluster headache headache brain diseases central nervous system diseases headache disorders headache disorders, primary nervous system diseases neurologic manifestations pain trigeminal autonomic cephalalgias
Sponsor: Eli Lilly and Company
Start date: 2016-07-13; Completion date: 2021-01-21
Enrollment: 165 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main purpose of this study is to assess the long-term safety and tolerability of galcanezumab administered up to once monthly in participants with episodic or chronic cluster headache who have completed study I5Q-MC-CGAL (NCT02397473) or study I5Q-MC-CGAM (NCT02438826).

Detailed description:

Arms: arm 1: Participants received 300 milligram (mg) Galcanezumab administered subcutaneously (SC) up to once a month.
Interventions: intervention 1: Galcanezumab
Intervention descriptions: intervention 1: Administered SC

Protocol documents:
Prot_000.pdf: 
 
 
 
 
Protocol I5Q-MC-CGAR(a) 
 
 
A Phase 3b Multicenter, Single-Arm, Open-Label Safety Study of 
LY2951742 (galcanezumab) in Patients with Episodic or Chronic 
Cluster Headache 
 
 
NCT02797951 
 
 
Approval Date: 15-May-2017 


I5Q-MC-CGAR(a) Clinical Protocol
Page 1
LY2951742 
Protocol I5Q-MC-CGAR
A Phase 3b Multicenter, Single-Arm, Open-Label Safety 
Study of LY2951742 (galcanezumab) in Patients with 
Episodic or Chronic Cluster Headache
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 
LY2951742 (galcanezumab), 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.
LY2951742 (galcanezumab)
Study CGAR is a Phase 3b multicenter, single-arm, open-label safety study of 
galcanezumab 300 mg in patients with episodic or chronic cluster headache who 
completed study I5Q-MC-CGAL or I5Q-MC-CGAM. 
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Approval Date: 15-May-2017 GMT


I5Q-MC-CGAR(a) Clinical Protocol
Page 2
LY2951742 
Table of Contents
Section
Page
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................14
3.3.
Benefit/Risk Assessment..............................................................................................15
4.
Objectives and Endpoints..................................................................................................16
5.
Study Design.....................................................................................................................17
5.1.
Overall Design .............................................................................................................17
5.2.
Number of Participants.................................................................................................19
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................19
6.
Study Population...............................................................................................................20
6.1.
Inclusion Criteria..........................................................................................................20
6.2.
Exclusion Criteria ........................................................................................................22
6.3.
Lifestyle Restrictions....................................................................................................24
6.4.
Screen Failures.............................................................................................................24
7.
Treatments........................................................................................................................26
7.1.
Treatments Administered .............................................................................................26
7.1.1.
Packaging and Labelling ......................................................................................26
7.1.2.
Medical Devices...................................................................................................27
7.2.
Method of Treatment Assignment ................................................................................27
7.2.1.
Selection and Timing of Doses.............................................................................27
7.3.
Blinding .......................................................................................................................27
7.4.
Dosage Modification....................................................................................................27
7.5.
Preparation/Handling/Storage/Accountability...............................................................27
7.6.
Treatment Compliance .................................................................................................27
7.7.
Concomitant Therapy...................................................................................................27
7.8.
Treatment After the End of the Study...........................................................................27
7.8.1.
Study Extensions..................................................................................................27
7.8.2.
Continued Access.................................................................................................28
7.8.3.
Special Treatment Considerations ........................................................................28
7.8.4.
Patient Follow-Up in Pragmatic Trials..................................................................28


I5Q-MC-CGAR(a) Clinical Protocol
Page 3
LY2951742 
8.
Discontinuation Criteria ....................................................................................................29
8.1.
Discontinuation from Study Treatment.........................................................................29
8.1.1.
Temporary Discontinuation from Study Treatment...............................................29
8.1.2.
Discontinuation of Inadvertently Enrolled ............................................................29
8.2.
Discontinuation from the Study....................................................................................29
8.3.
Lost to Follow-Up........................................................................................................30
9.
Study Assessments and Procedures ...................................................................................31
9.1.
Efficacy Assessments...................................................................................................31
9.1.1.
Appropriateness of Assessments ..........................................................................31
9.2.
Adverse Events ............................................................................................................31
9.2.1.
Serious Adverse Events........................................................................................32
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................33
9.2.1.2.
Adverse Event Monitoring with the Columbia-Suicide 
Severity Rating Scale, Self-Harm Supplement Form, and 
Self-Harm Follow-up Form ............................................................................33
9.2.2.
Complaint Handling.............................................................................................33
9.3.
Treatment of Overdose.................................................................................................34
9.4.
Safety...........................................................................................................................34
9.4.1.
Electrocardiograms ..............................................................................................34
9.4.2.
Vital Signs ...........................................................................................................34
9.4.3.
Laboratory Tests ..................................................................................................35
9.4.4.
Safety Monitoring ................................................................................................35
9.4.5.
Samples for Immunogenicity Research.................................................................35
9.5.
Pharmacokinetics .........................................................................................................36
9.6.
Pharmacodynamics ......................................................................................................36
9.7.
Pharmacogenomics and Genetics .................................................................................36
9.8.
Biomarkers...................................................................................................................36
9.9.
Health Economics ........................................................................................................36
9.10. Cluster Headache Attack Assessments .........................................................................37
10.
Statistical Considerations ..................................................................................................38
10.1. Sample Size Determination ..........................................................................................38
10.2. Populations for Analyses..............................................................................................38
10.3. Statistical Analyses ......................................................................................................38
10.3.1.
General Statistical Considerations ........................................................................38
10.3.2.
Treatment Analyses..............................................................................................38
10.3.2.1.
Patient Disposition..........................................................................................38
10.3.2.2.
Patient Characteristics ....................................................................................39
10.3.2.3.
Concomitant Therapy .....................................................................................39


I5Q-MC-CGAR(a) Clinical Protocol
Page 4
LY2951742 
10.3.3.
Efficacy Analyses ................................................................................................39
10.3.4.
Safety Analyses....................................................................................................39
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................40
10.3.6.
Other Analyses.....................................................................................................40
10.3.6.1.
Health Economics...........................................................................................40
10.3.7.
Immunogenicity Analyses....................................................................................41
10.3.8.
Interim Analyses..................................................................................................41
11.
References ........................................................................................................................42
12.
Appendices .......................................................................................................................44


I5Q-MC-CGAR(a) Clinical Protocol
Page 5
LY2951742 
List of Tables
Table
Page
Table 2.1.
Schedule of Activities, Protocol I5Q-MC-CGAR...........................................11
Table 4.1.
Objectives and Endpoints...............................................................................16


I5Q-MC-CGAR(a) Clinical Protocol
Page 6
LY2951742 
List of Figures
Figure
Page
Figure 2.1.
CGAR visit flow diagram. .............................................................................10


I5Q-MC-CGAR(a) Clinical Protocol
Page 7
LY2951742 
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................45
Appendix 2.
Clinical Laboratory Tests...............................................................................49
Appendix 3.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................50
Appendix 4.
Study Governance Considerations..................................................................51
Appendix 5.
Protocol Amendment Summary:  I5Q-MC-CGAR(a).....................................54


I5Q-MC-CGAR(a) Clinical Protocol
Page 8
LY2951742 
1.
Synopsis
Title of Study:
A Phase 3b Multicenter, Single-Arm, Open-Label Safety Study of LY2951742
(galcanezumab) in Patients with Episodic or Chronic Cluster Headache
Rationale:
Galcanezumab is a humanized monoclonal antibody that selectively binds to and neutralizes 
calcitonin gene-related peptide (CGRP) that has been identified for clinical development in pain 
conditions relevant to the CGRP pathway such as migraine and cluster headache. The 
similarities between migraine and cluster headache, the role of CGRP in both disorders, and the 
clinical efficacy observed with galcanezumab to date for the preventive treatment of migraine 
support the evaluation of galcanezumab for the treatment of cluster headache.
The aim of this study is to assess the long-term safety and tolerability of galcanezumab 300 mg 
administered up to once monthly in episodic or chronic cluster headache patients who have 
completed Study I5Q-MC-CGAL (CGAL) or Study I5Q-MC-CGAM (CGAM).
Objective(s)/Endpoints:
The primary objective of this study is to evaluate the safety of open-label galcanezumab within 
the context of expected medical practice in eligible patients with episodic or chronic cluster 
headache. Safety will be assessed using treatment emergent adverse events (TEAEs), serious 
adverse events (SAEs), as well as suicidal ideation and behaviors utilizing the Columbia-Suicide 
Severity Rating Scale (C-SSRS).
Summary of Study Design:
Briefly, Study I5Q-MC-CGAR (CGAR) is a Phase 3b single-arm, open-label safety study of 
galcanezumab 300 mg in outpatients with episodic or chronic cluster headache who completed 
Study CGAL or Study CGAM.  This study will consist of 2 study phases (SP): SP I is the 
screening phase to confirm patients meet the inclusion/exclusion criteria, and SP II is the 
open-label treatment phase during which patients can receive galcanezumab 300 mg
administered subcutaneously (SC) up to once a month.  Within the paradigm of a once-monthly 
dosing regimen, the decision to dose at each monthly interval will be determined by the 
investigator.
Treatment Arms and Duration:
One treatment arm: galcanezumab 300 mg administered SC up to once a month as determined 
by the study investigator based on clinical symptoms and response.
Number of Patients:
This is an open-label safety study for patients who previously enrolled in and completed Study 
CGAL or Study CGAM.  Therefore, the sample size is determined by the number of patients 
completing Studies CGAL and CGAM who choose to enroll in this study.


I5Q-MC-CGAR(a) Clinical Protocol
Page 9
LY2951742 
Statistical Analysis:
Unless otherwise specified, analyses will be conducted on the evaluable analysis set, which 
includes all enrolled patients receiving at least 1 dose of the investigational product.
The primary analyses will include summaries of TEAEs, SAEs, and suicidal ideation and 
behaviors assessed by solicited questioning using the C-SSRS.


I5Q-MC-CGAR(a) Clinical Protocol
Page 10
LY2951742 
2. Schedule of Activities
*Approximately 1 week after the 1st dose at Month 0, a Telephone visit  will occur (Use Event List G). 
**If treatment was halted per protocol during the study, the following procedures:  ECG, immunogenicity, PK, hematology, clinical 
chemistry, HbA1c and urine pregnancy, are to be completed prior to reinitiation of dosing (see Section 5.1 for additional details).
Figure 2.1.
CGAR visit flow diagram.


I5Q-MC-CGAR(a) Clinical Protocol
Page 11
LY2951742 
Table 2.1.
Schedule of Activities, Protocol I5Q-MC-CGAR
Study Phase
SP I
SP II
Dosing Visits
Non-dosing visits
Events
Event List A
Event List B
Event List C
Event List D
Event List E
Event List F
Event List G
Visit
Visit 1a,b,c,d
Month 0
1st Dose
Month 1
Month 6 and 
every 6 Months 
thereafter 
(e.g., Month 12, 
18…)
Months not 
listed in Event 
List B, C, or D
(e.g., Month 2, 
3, 4, 5, 7, 8…)
The first visit 
after a dose
Dose is not 
administered;
Telephone visit
Informed consent
X
Inclusion/exclusion 
criteria
X
Medical history and 
pre-existing conditions
X
Electrocardiograme
X
X
X
X
Physical examinationf
X
X
X
X
X
X
Weight
X
X
X
Waist and hip 
circumference
X
Vitalsg
X
X
X
X
X
X
Hematologye
X
X
X
Clinical chemistrye
X
X
X
Urinalysise
X
X
X


I5Q-MC-CGAR(a) Clinical Protocol
Page 12
LY2951742 
Study Phase
SP I
SP II
Dosing Visits
Non-dosing visits
Events
Event List A
Event List B
Event List C
Event List D
Event List E
Event List F
Event List G
Visit
Visit 1a,b,c,d
Month 0
1st Dose
Month 1
Month 6 and 
every 6 Months 
thereafter 
(e.g., Month 12, 
18…)
Months not 
listed in Event 
List B, C, or D
(e.g., Month 2, 
3, 4, 5, 7, 8…)
The first visit 
after a dose
Dose is not 
administered;
Telephone visit
HbA1C
e
X
X
X
FSH
X
Serum pregnancyk
X
X
Urine pregnancy teste, k
(performed by site)
X
X
Urine drug screenk
X
Immunogenicitye
X
X
X
X
PK samplinge
X
X
X
X
PGI-I
X
X
X
EQ-5D-5L
X
X
X
X
X
Cluster headache status
X
X
X
X
X
X
C-SSRS/SHSF, SHFUh
X
X
X
X
X
X
AEs
Xi
X
X
X
X
X
X
SAEs
X
X
X
X
X
X
X


I5Q-MC-CGAR(a) Clinical Protocol
Page 13
LY2951742 
Study Phase
SP I
SP II
Dosing Visits
Non-dosing visits
Events
Event List A
Event List B
Event List C
Event List D
Event List E
Event List F
Event List G
Visit
Visit 1a,b,c,d
Month 0
1st Dose
Month 1
Month 6 and 
every 6 Months 
thereafter 
(e.g., Month 12, 
18…)
Months not 
listed in Event 
List B, C, or D
(e.g., Month 2, 
3, 4, 5, 7, 8…)
The first visit 
after a dose
Dose is not 
administered;
Telephone visit
Concomitant medications
X
X
X
X
X
X
Administer LY2951742j
X
X
X
X
Abbreviations:  AE = adverse event; C-SSRS = Columbia-Suicide Severity Rating Scale; EQ-5D-5L = European quality 5-dimensions 5-levels; FSH = follicle 
stimulating hormone; HbA1C = hemoglobin A1C; ND = not done; PGI-I = Patient Global Impression of Improvement; PK = pharmacokinetics; SAE = serious 
adverse event; SHFU = Self-Harm Follow-up Form; SHSF = Self-Harm Supplement Form; V = visit.
a
If the last visit of the parent study is also the first visit of Study CGAR, then ECGs, vitals, weight, hematology, clinical chemistry, urinalysis, HbA1C, and serum pregnancy, C-SSRS, and 
SHSF/SHFU from the last visit of the parent study will also be used for the first visit of CGAR.  All other study procedures in Event List A need to be completed at V1 of CGAR.
b
If the last visit of the parent study is ≤2 weeks from V1 of CGAR, the hematology, chemistry, HbA1C, and urinalysis do not need to be repeated.  All other study procedures in Event List A need to 
be completed at V1 of CGAR.
c
If the last visit of the parent study is >2 weeks from V1 of CGAR, all study procedures in Event List A need to be completed at the first visit of CGAR. 
d
After V1, if V2 does not occur within 3 months of V1 (e.g., patient enters V1 in remission), prior to V2 an ECG, hematology, clinical chemistry, urinalysis, urine drug screen, HbA1C, and serum 
pregnancy must be collected and eligibility confirmed again prior to dosing at V2.
e
If treatment was halted per protocol during the study, the following procedures:  ECG, immunogenicity, PK, hematology, clinical chemistry, HbA1c and urine pregnancy, are to be completed prior to 
reinitiation of dosing (see Section 5.1 for additional details).
f
Directed physical examination only if needed.
g
Vital signs include body temperature, blood pressure, and pulse. Blood pressure and pulse will be measured in triplicate in the sitting position and should be measured prior to blood draws.
h
The C-SSRS and SHSF (SHFU when applicable) will be completed at scheduled and unscheduled office visits.
i
At V1, record AEs that are on-going from the previous trial.
j
Patients should remain in the office for 30 minutes of observation following the first LY2951742 injection of the study; injections of LY2951742 are to occur after all other visit procedures are 
completed.
k
May be repeated during the study at the discretion of the investigator.


I5Q-MC-CGAR(a) Clinical Protocol
Page 14
LY2951742 
3.
Introduction
3.1.
Study Rationale
Study CGAR is a Phase 3b study to assess the long-term safety and tolerability of galcanezumab
300 mg in patients with episodic or chronic cluster headache who have completed one of the 
Phase 3 double-blind, placebo-controlled studies, CGAL or CGAM.
Study CGAR will implement a dosing strategy to more closely approximate what may occur in 
clinical practice.  For each patient, the study investigator will determine whether or not to dose 
galcanezumab 300 mg at each monthly interval based on clinical symptoms and response.  
Dosing will be no more frequent than once per month, and the investigator may choose to not 
dose galcanezumab for 1 or more months at their clinical discretion based on clinical efficacy.  
As such, some patients may receive monthly long-term treatment with galcanezumab for a period 
of months or years during the study, while others may have 1 or more months of galcanezumab
dose-free intervals based on the investigator’s judgment of clinical efficacy.  
3.2.
Background
Cluster headache is a rare but disabling primary headache disorder characterized by episodic 
attacks of intense unilateral headache and the frequent association of autonomic symptoms such 
as lacrimation, conjunctival injection, and nasal congestion (International Classification of 
Headache Disorders, Third edition, beta version [ICHD-3 2013]).  The diagnosis of cluster 
headache is distinctly recognized and defined ICHD-3 (2013).
There are significant unmet needs for just about every clinical aspect of the patient with cluster 
headache, particularly related to the severity of the disease and treatment options.  The majority 
of patients experiencing cluster headache attacks rate their pain intensity as near to or at the 
worst pain imaginable (using a Visual Analog Scale [VAS] 10-cm scale; Torelli and Manzoni 
2003). Regarding treatment options, two main treatment modalities are typically used:  
acute/abortive treatments (used at the onset of individual cluster headache attacks to abort the 
attack) and prophylactic/preventive treatments (aimed to reduce cluster headache attack 
frequency).  In the United States, there are no approved preventive medications.
Calcitonin gene-related peptide is a 37-amino acid neuropeptide member of a family of peptides 
that includes amylin, adrenomedullin and calcitonin.  Calcitonin gene-related peptide is one of 
the most abundant peptides within the nervous system (McCarthy and Lawson 1990), and is 
highly expressed in trigeminal ganglion neurons.  The association of CGRP with cluster 
headache was demonstrated in 2 studies of patients with either spontaneous or induced cluster 
headache attacks who were found to have elevated CGRP levels compared to controls 
(Edvinsson and Goadsby 1994; Fanciullacci et al.1995; Fanciullacci et al. 1997).  The elevated 
CGRP levels were normalized after successful treatment with SC sumatriptan, oxygen 
inhalation, or spontaneous recovery.
Galcanezumab is a humanized monoclonal antibody that selectively binds to and neutralizes 
CGRP.  Galcanezumab has been identified for clinical development in pain conditions relevant 


I5Q-MC-CGAR(a) Clinical Protocol
Page 15
LY2951742 
to the CGRP pathway such as migraine; and in completed studies to date, galcanezumab was 
shown to alter plasma CGRP concentrations, which is consistent with the binding of the antibody 
(galcanezumab) to CGRP (Investigator’s Brochure [IB] Section 3.1).
To date, more than 380 clinical trial participants with migraine and 84 healthy volunteers have 
been exposed to galcanezumab at single doses up to 600 mg and multiple doses up to 300 mg in 
5 clinical trials of galcanezumab. In studies of patients with migraine (Studies I5Q-MC-ART1 
[ART-01] and I5Q-MC-CGAB [CGAB]), efficacy data have demonstrated that galcanezumab
had significantly greater mean reductions than placebo in migraine headache days and other 
efficacy parameters. Across clinical studies of galcanezumab, assessment of TEAEs indicates 
that galcanezumab has been well tolerated in both healthy subjects and in patients with episodic 
migraine. The AEs generally have been mild to moderate in severity. In the completed studies 
of patients with migraine, the most frequently reported TEAEs in either study included injection-
site pain, upper respiratory tract infection, abdominal pain, dizziness, injection-site erythema, 
rash, hypertension, and nasopharyngitis. Analyses of laboratory values and cardiovascular 
monitoring of the clinical studies have shown no clinically important changes in tested 
parameters (IB Section 3.2).
3.3.
Benefit/Risk Assessment
More information about the known and expected benefits, risks, and reasonably anticipated AEs
of galcanezumab may be found in the IB.  Information on AEs expected to be related to the 
investigational product may be found in Section 7 (Development Core Safety Information) of the 
IB.  Information on SAEs expected in the study population independent of drug exposure and 
that will be assessed by the sponsor in aggregate periodically during the course of the study, may 
be found in Section 6 (Effects in Humans) of the IB.


I5Q-MC-CGAR(a) Clinical Protocol
Page 16
LY2951742 
4.
Objectives and Endpoints
Table 4.1 shows the objectives and endpoints of the study.
Table 4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the safety of open-label galcanezumab
within the context of expected medical practice in 
eligible patients with episodic or chronic cluster 
headache.
Analysis of:

TEAEs

SAEs

Suicidal ideation and behaviors assessed by 
solicited questioning using the C-SSRS
Secondary
To characterize the reasons for discontinuation and AEs
of interest for galcanezumab.
Discontinuation rates
To characterize the immunogenicity of galcanezumab.
Analysis of:

Injection-site reactions

Allergy/hypersensitivity

Infections

The development and consequences of ADAs 
to galcanezumab, their relationship with AEs, 
and neutralizing ADAs to galcanezumab
Tertiary
To evaluate the effectiveness of galcanezumab.

The proportion of patients reporting a score of 
1 (“very much better”) or 2 (“much better”) on 
the PGI-I 1 month after receiving their first 
dose will be reported.
To evaluate the effect of galcanezumab on health 
values.
EQ-5D-5L Analysis of:

Health state index values

Each dimension of the descriptive system and 
dichotomized level responses

EQ-VAS current health score

Correlations with PGI-I, cluster headache status
Abbreviations: ADA = anti-drug antibodies; C-SSRS = Columbia-Suicide Severity Rating Scale; EQ-5D-5L 
Analysis = European quality 5-dimensions 5-levels; EQ-VAS = European Quality Visual Analogue Scale; PGI-I 
= Patient Global Impression of Improvement; SAE = serious adverse event; TEAE = treatment-emergent adverse 
event.


I5Q-MC-CGAR(a) Clinical Protocol
Page 17
LY2951742 
5.
Study Design
5.1.
Overall Design
Study CGAR is a Phase 3b single-arm, open-label safety study of galcanezumab 300 mg in 
outpatients with episodic or chronic cluster headache who completed Study CGAL or 
Study CGAM.
Please refer to the Protocol Operations Manual for information regarding the schedule of 
activities, study design, study tools, and patient scenario examples.
The study will consist of 2 SP:

SP I is the screening phase to confirm patients meet the inclusion/exclusion criteria.

SP II is the open-label treatment phase during which patients can receive galcanezumab
300 mg administered subcutaneously (SC) up to once a month.


I5Q-MC-CGAR(a) Clinical Protocol
Page 18
LY2951742 
Study Phase I: SP I is the screening phase. Patients will sign an informed consent document 
prior to completing any study-related screening procedures. SP I is the time from Visit (V)1 to 
V2.  The minimum timeframe for SP1 needs to allow sufficient time for patients to washout of 
any excluded medications and to review subject eligibility. Visit 1 will be considered complete 
when the last procedure of the screening assessment for the patient is completed.  Once Study 
CGAR is open for enrollment, potentially eligible patients may enter screening directly from the 
parent study, CGAL or CGAM.  If a patient is not experiencing cluster headache attacks (e.g., in 
remission) they may wait to enter screening for CGAR until they anticipate experiencing or are 
experiencing a cluster headache attack.  If patients had completed the parent study, CGAL or 
CGAM, prior to Study CGAR being open for enrollment, potentially eligible patients may still 
enter screening for Study CGAR. Study procedures for V1 (Event List A) of Study CGAR will 
be completed as follows:

If the last visit of the parent study is also the first visit of Study CGAR, then 
electrocardiograms (ECGs), vitals, weight, hematology, clinical chemistry, urinalysis, 
hemoglobin A1C (HbA1C), and serum pregnancy, C-SSRS, and Self-Harm Supplement 
Form/ Self-Harm Follow-up Form (SHSF/SHFU) from the last visit of the parent study 
will also be used for the first visit of Study CGAR.

If the last visit of the parent study is ≤2 weeks from V1 of Study CGAR, the hematology, 
chemistry, HbA1C, and urinalysis do not need to be repeated.

If the last visit of the parent study is >2 weeks from V1 of Study CGAR, all study 
procedures in Event List A need to be completed at the first visit of Study CGAR.
Note:  After V1, if V2 does not occur within 3 months of V1 (e.g., patient enters V1 in 
remission), prior to V2 an ECG, hematology, clinical chemistry, urinalysis, urine drug screen 
(UDS), HbA1C, and serum pregnancy must be collected and eligibility confirmed prior to dosing
at V2 (see footnote “d” in the SOA).
Study Phase II: SP II is the single-arm open-label treatment phase during which patients can 
receive galcanezumab 300 mg administered SC up to once a month. If a patient meets all 
eligibility requirements, a urine pregnancy screen will be conducted at the first dosing visit, prior 
to dosing to confirm that a female patient is not pregnant before administering investigational 
product.  Following the first dose of galcanezumab, the patient should remain in the office for 
30 minutes of observation. The site will have a scheduled telephone visit (V3) with the patient 
approximately 1 week after the first investigational product administration to collect 
spontaneously reported AEs.
Every month, the decision whether to administer a monthly dose will be based upon the study 
investigator’s judgment, which is not limited to, but includes assessment of the patient’s clinical 
symptoms and response as follows:

Dosing is up to once monthly; more frequent dosing is not allowed.  The full 300 mg 
dose is to be administered, changing the dose amount is not allowed. 

If the patient remits and dosing is halted, the patient may remain in the study, but they 
should have an office visit 1 month after the last dose to complete the procedures listed in 


I5Q-MC-CGAR(a) Clinical Protocol
Page 19
LY2951742 
Event List F (Table 2.1). Dosing in this scenario may be reinitiated at the study 
investigator’s discretion.

Monthly telephone visits should be completed for patients who are not being dosed, but 
remain in the study (e.g., in remission).

If dosing is temporarily interrupted due to a potential safety concern, dosing may be re-
initiated at the study investigator’s discretion following a discussion and agreement 
between the study investigator and Lilly Medical that re-initiation of dosing is 
appropriate.
o
At the office visit prior to re-initiation of dosing the following procedures:  
ECG, immunogenicity, pharmacokinetics (PK), hematology, clinical chemistry, 
HbA1c and urine pregnancy are to be collected.  The urine pregnancy must be 
negative and the ECG should be evaluated for safety prior to dosing.  
5.2.
Number of Participants
Only patients who previously enrolled in and completed Study CGAL or Study CGAM are 
eligible for this study.  Therefore, the maximum number of eligible participants is determined by 
the number of participants completing Studies CGAL and CGAM.
5.3.
End of Study Definition
The study will continue in a specific region until any one of the following criteria is met:

Sponsor decision

Nonapproval from a regulatory agency in the country/region in which the patient is 
enrolled
5.4.
Scientific Rationale for Study Design
Please refer to Section 3.1 for further information.
5.5.
Justification for Dose
The dose level proposed for the study of galcanezumab in cluster headache is 300 mg 
administered once monthly. Based on inhibition of capsaicin-induced dermal blood flow 
(CIDBF) and pharmacokinetic/pharmacodynamic (PK/PD) modeling of plasma CGRP 
concentrations (target engagement) from prior studies, it is presumed that this dose regimen will 
provide a high degree of pharmacological activity (greater than 90% effective in inhibiting 
CIDBF; about 90% decrease from baseline in unbound plasma CGRP concentrations), and be 
sufficient to test the effectiveness of galcanezumab for the treatment of cluster headache. A dose 
of 300 mg once monthly is predicted to replicate the exposure and have the same effect on 
CIDBF and unbound plasma CGRP as 150 mg every 2 weeks (Q2W), which yielded evidence of 
efficacy in migraine (Study ART-01). The safety and tolerability of galcanezumab supports 
dosing at 300 mg once monthly.  Additionally, the parent trials, Study CGAL and Study CGAM,
utilized galcanezumab 300 mg once monthly dosing.


I5Q-MC-CGAR(a) Clinical Protocol
Page 20
LY2951742 
6.
Study Population
Patients diagnosed with episodic or chronic cluster headache that were enrolled in and
completed one of the parent studies, Study CGAL or Study CGAM, are potentially eligible for 
this study.
If the sponsor or investigator identifies a patient who did not meet enrollment criteria for Study 
CGAR and was inadvertently enrolled, a discussion must occur between the sponsor clinical 
research physician (CRP) and the investigator to determine if the patient may be considered for 
Study CGAR.  If both agree it is medically appropriate for the patient to be considered for Study 
CGAR, the decision must be documented by the investigator.
All patients must meet the following selection criteria.  Eligibility of patients for study 
enrollment will be based on medical history, physical examination, clinical laboratory tests, 
ECG, and the inclusion and exclusion criteria described below.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
considered for rescreen once, for selected criteria, with approval from Eli Lilly and Company 
(hereafter Lilly) Medical (see below).
Prospective approval of protocol deviations to enrollment criteria, also known as protocol 
waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
1. Patients who participated in and completed either Study CGAL or Study CGAM.  A study
completer is defined as follows:
a.
Study CGAL: a patient who has completed the double-blind treatment and post-
treatment follow-up phases.
b. Study CGAM: a patient who has completed the double-blind treatment, open-label 
extension and post-treatment follow-up phases. However, if a patient entered Study 
CGAM prior to Study CGAR being open for enrollment, they will be considered a 
completer if they completed the double-blind treatment and post-treatment follow-up 
phases (e.g., opted not to participate in the open-label extension).
2. Investigator judges the patient as reliable to follow all study procedures, keep all study 
visits, and be compliant with study requirements.
3. Reproduction:
a. Women of child-bearing potential may participate in the study.
i. Women of child-bearing potential must test negative for pregnancy (based on a 
urine pregnancy test) at the time of enrollment and must agree to use either 1
highly effective method of contraception or a combination of 2 effective 
methods of contraception during the study. Women may choose to use a 
double barrier method of contraception. Barrier methods without concomitant 
use of a spermicide are not reliable or an acceptable method. Thus, each 
barrier method must include use of a spermicide. It should be noted that the 


I5Q-MC-CGAR(a) Clinical Protocol
Page 21
LY2951742 
use of male and female condoms as a double barrier method is not considered 
acceptable due to the high failure rate when these methods are combined.
b. Women not of child-bearing potential may participate in the study and include those 
who are:
i. Infertile due to surgical sterilization (at least 6 weeks after hysterectomy, 
bilateral oophorectomy or tubal ligation), congenital anomaly such as mullerian 
agenesis, or
ii. Post-menopausal, which is defined as:
a.
A woman at least 50 years of age with an intact uterus, not on hormone 
therapy, who has had either
i.
cessation of menses for at least 1year, or
ii.
at least 6 months of spontaneous amenorrhea with a follicle-stimulating 
hormone (FSH) level >40 mIU/mL; or
b. A woman 55 or older not on hormone therapy who has had at least 
6 months of spontaneous amenorrhea; or
c.
A woman at least 55 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy.
c. Male patients agree to use at least 1 effective method of contraception during the study.
Note: If a male or female patient remits during the study and discontinues treatment, 
but remains in the study, they must continue to use a birth control as outlined above. 
At study termination, women and men must use birth control for at least 5 months 
following their last dose.
Please refer to the Protocol Manual of Operations for a list of the  methods of 
contraception.
4. Throughout the study, agree to refrain from the use of drugs of abuse per United States 
Federal Guidelines (Schedule I) such as, but not limited to, cannabinoids, cannabis, 
psilocybin (mushrooms), Lysergic acid diethylamide (LSD) and 2-bromo-LSD.
5. 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 (for example, Facebook, Twitter, LinkedIn, 
Google+, etc.) until the entire trial has completed or you are otherwise informed by the study 
investigator.
6. Have given written informed consent.


I5Q-MC-CGAR(a) Clinical Protocol
Page 22
LY2951742 
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
7. Current enrollment in, or discontinuation within the last 30 days prior to V1 from, a clinical 
trial (with the exception of Study CGAL or Study CGAM) involving any investigational 
product or device, or concurrent enrollment in any other type of medical research judged 
not to be scientifically or medically compatible with this study.
a.
Adequate washout (≥5 half-lives) of any investigational product is also required and 
may require >30 days depending on the half-life of the investigational product. 
8. Use of therapeutic antibodies (except galcanezumab) during the course of the study 
(adalimumab, infliximab, trastuzumab, bevacizumab, etc.).  Prior use of other therapeutic 
antibodies is allowed if an adequate washout has occurred (≥5 half-lives) prior to V2.
9. Lifetime history of migraine variants that could implicate or could be confused with 
ischemia; specifically, hemiplegic (sporadic or familial) migraine, ophthalmoplegic 
migraine, and basilar-type migraine defined by ICHD-3 beta.
10. Taking excluded medication(s) at V2.  Excluded medications require an adequate washout 
(≥5 half-lives) prior toV2.  The list of excluded medications is provided separately from the 
protocol.
11. 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.  Patients with major depressive disorder or generalized anxiety disorder, 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 medication(s).
12. Are considered by the investigator to be at significant risk for suicide.
13. Women who are pregnant or nursing.
14. Any of the following cardiovascular-related conditions are exclusionary:
a.
Since enrolling in Study CGAL or Study CGAM or prior to V2 (enrollment), have 
ECGs showing acute abnormalities of:
i. evidence of delayed ventricular repolarization including but not limited to a 
corrected QT (Fridericia’s QT interval [QTcF]) interval >470 msec for women 
and >450 for men, and/or
ii. evidence of atrioventricular (AV) depolarization of PR>220, or conduction delay 
of QRS>120, and/or
iii. evidence of ischemia or any of the qualitative findings indicative of ST or J-point 
elevation, excluding those findings consistent with early repolarization (non-
ischemic).


I5Q-MC-CGAR(a) Clinical Protocol
Page 23
LY2951742 
NOTE:  Patients who meet 1 of the 14(a) ECG criteria during Study CGAL or Study 
CGAM may enroll in Study CGAR if the study investigator deems the finding not 
clinically significant.
b. History of myocardial infarction (MI), unstable angina (UA), percutaneous coronary 
intervention, coronary artery bypass graft, deep vein thrombosis/pulmonary embolism 
since enrolling in Study CGAL or Study CGAM and prior to V2 of Study CGAR, or 
have planned cardiovascular surgery or percutaneous coronary angioplasty or surgery 
for peripheral arterial disease.
c.
Any lifetime history of vasospastic angina or stroke, or history of emergency room 
visit for chest pain in which an ischemic or cardiac event was not ruled out since 
enrolling in Study CGAL or Study CGAM and prior to V2 of Study CGAR.
d. Clinical evidence of peripheral vascular disease (e.g., Buerger’s Disease) or a 
diagnosis of Raynaud’s Disease or Raynaud’s Phenomenon.
e.
Have any history of intracranial or carotid aneurysm, intracranial hemorrhage, or 
stroke.
f.
Have uncontrolled high blood pressure characterized by systolic blood pressure 
>160 mmHg or diastolic blood pressure >100 mmHg on 2 or more blood pressure 
assessments prior to V2 of Study CGAR.
NOTE:  Patients who meet the 14(f) blood pressure criteria during Study CGAL or 
Study CGAM may enroll in Study CGAR if the study investigator deems the finding 
not clinically significant.
15. Any of the following medical conditions are exclusionary:
a.
Have a lifetime history of seizures (except for childhood febrile seizures).
b. Have a history or presence of any other medical illness including but not limited to 
any cardiovascular, hepatic, respiratory, hematological, endocrine, psychiatric or 
neurological disease, or any clinically significant laboratory abnormality, that in the 
judgment of the investigator indicates a medical problem that would preclude study 
participation.
c.
Prior to V2, patients who have an elevation of ≥2× the upper limit of normal (ULN)
for alanine aminotransferase (ALT), or ≥1.5× ULN for total bilirubin (TBL) or 
alkaline phosphatase (ALP) may be retested.  The patient’s results must be discussed 
with Lilly Medical and judged not clinically significant prior to enrollment.
NOTE:  Patients with TBL ≥1.5× ULN are not excluded if they meet all of the 
following criteria for Gilbert syndrome:
1. Bilirubin is predominantly indirect (unconjugated) at screening (direct 
bilirubin within normal limits)
2. Absence of liver disease
3. ALT, aspartate aminotransferase (AST), and ALP ≤1× ULN at screening


I5Q-MC-CGAR(a) Clinical Protocol
Page 24
LY2951742 
4. Hemoglobin not significantly decreased at screening
d. Patients with a history of an intracranial tumor or head trauma must be discussed and 
judged not to indicate a medical problem that would preclude study participation by 
Lilly Medical prior to enrollment.
16. Any of the following drug- or alcohol-related conditions are exclusionary:
a.
History of use of psilocybin (mushrooms), LSD, or 2-bromo-LSD within 2 months 
prior to V2.
b. Patients with a positive UDS for any substances of abuse prior to enrollment are 
excluded.  Note:  One retest may be performed if the UDS is positive for any 
prescribed substance. However, the results of the retest must be negative at or prior 
to enrollment at V2.
c.
Drug, alcohol, opioid, or barbiturate abuse/dependence since completing either 
Study CGAL or Study CGAM (excessive or habitual use as judged by the 
investigator), or currently using drugs of abuse (including, but not limited to opioids, 
barbiturates and cannabis), or any prescribed or over-the-counter medication in a 
manner that the investigator considers indicative of abuse/dependence.  This 
exclusion criterion does not apply to tobacco and caffeine.
17. Employees of Lilly or investigational site personnel directly affiliated with this study and 
their immediate families.  Immediate family is defined as a spouse, parent, child or sibling, 
whether biological or legally adopted.
18. Known hypersensitivity to multiple drugs, monoclonal antibodies or other therapeutic 
proteins, or to galcanezumab or to any of the inactive ingredients.
19. Patients who were inadvertently enrolled in study CGAL/CGAM may not be eligible for 
enrollment in CGAR.  Approval from Lilly Medical is required.
6.3.
Lifestyle Restrictions
Patients are encouraged to abstain from alcohol consumption during active cluster periods.
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 following criteria:

Inclusion Criteria 4

Exclusion Criteria 7

Exclusion Criteria 8; patients with inadequate washout may be rescreened following an 
appropriate washout period.

Exclusion Criteria 10; patients with inadequate washout may be rescreened following an 
appropriate washout period.


I5Q-MC-CGAR(a) Clinical Protocol
Page 25
LY2951742 

Exclusion Criteria 11; patients with unstable mood or anxiety disorders may rescreen
once that disorder is appropriately stabilized.

Exclusion Criteria 12; these screen-fail patients may be considered for rescreen if the
following conditions are met:
o
The patient was referred to an appropriate mental health professional and received 
treatment as necessary.
o
At least 6 months has elapsed since the screen-fail.
o
Are not considered by the investigator to be at significant risk for suicide at time
of rescreening.

Exclusion Criteria 13

Exclusion Criterion 14(f); patients with uncontrolled high blood pressure may be 
considered for rescreen once their blood pressure is controlled in the opinion of the 
investigator and at <160/100; any use of antihypertensive medication and dose must be
stable for at least 2 months prior to V2.

Exclusion Criteria 16(b):  If a patient fails eligibility due to a positive UDS, the patient 
may be considered for rescreen.


I5Q-MC-CGAR(a) Clinical Protocol
Page 26
LY2951742 
7. Treatments
7.1.
Treatments Administered
All eligible subjects will receive galcanezumab 300 mg during the treatment phase (SP II).  The 
treatment will be administered as three injections each containing 100 mg/1.0 mL by site 
personnel, during SPII.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the site personnel

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

returning all unused medication to Lilly or its designee at the end of the study
Note: In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose clinical trial materials.
Possible injection sites include the abdomen, thigh, and upper arm. Buttocks may also be used,
if more appropriate for SC injection than the other sites.
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 so that the situation can be assessed.
7.1.1. Packaging and Labelling
Galcanezumab for injection, 100 mg/1.0 mL, will be supplied by the sponsor as disposable 
manual prefilled syringes (during SP II) in accordance with Current Good Manufacturing 
Practice (cGMP).
Packaging, Preparation, Labeling, and Storage
Galcanezumab solution for injection will be supplied by the sponsor or its designee in 
accordance with cGMP. Galcanezumab will be supplied as an injectable solution in 1-mL, 
single-dose, disposable manual syringes.  Each syringe of galcanezumab will be designed to
deliver 100 mg of galcanezumab.  The disposable manual prefilled syringes of galcanezumab for 
injection, 100 mg/1.0 mL should be stored in the refrigerator (2° C to 8° C).  The disposable 
manual prefilled syringes should be removed from the refrigerated storage and allowed to 
equilibrate to room temperature for approximately 30 minutes before administration.
Administration of Galcanezumab Using Disposable Manual Prefilled Syringe
Injections will be administered by the clinical staff.  A dose will consist of three 1-mL disposable 
manual prefilled syringes, with each syringe containing 100 mg of galcanezumab, for a total of 
300 mg galcanezumab.


I5Q-MC-CGAR(a) Clinical Protocol
Page 27
LY2951742 
7.1.2. Medical Devices
The manufactured medical device provided for use in this study is a disposable manual prefilled 
syringe.
7.2.
Method of Treatment Assignment
All patients will receive the same treatment: galcanezumab 300 mg.
7.2.1. Selection and Timing of Doses
Investigational product (galcanezumab) will be administered as 3 SC injections of not more than 
once monthly during SP II at the discretion of the investigator.  Less than 28 days between doses 
is a protocol violation.
Investigational product injections should only be administered after all other study procedures 
are completed for the given visit.
7.3.
Blinding
This is an open-label study.
7.4.
Dosage Modification
Not applicable.
7.5.
Preparation/Handling/Storage/Accountability
Please refer to Section 7.1.1.
7.6.
Treatment Compliance
To ensure treatment compliance, investigational product will be administered by site personnel.  
To document treatment administration each injection must be documented in the electronic case 
report form (eCRF) and follow the Schedule of Activities (Table 2.1).
7.7.
Concomitant Therapy
The list of allowed/not allowed medications and procedures is provided separately in the 
Protocol Operations Manual.  Patients should be instructed to consult with the investigator or 
study coordinator at the site before taking any new prescribed medications, over-the-counter 
(OTC) medications, or supplements. If the need for other concomitant medication arises, 
inclusion or continuation of the patient in the study may be at the discretion of the investigator 
after consultation with Lilly CRP/CRS or delegate.
7.8.
Treatment After the End of the Study
7.8.1. Study Extensions
Not applicable.


I5Q-MC-CGAR(a) Clinical Protocol
Page 28
LY2951742 
7.8.2. Continued Access
Not applicable.
7.8.3.Special Treatment Considerations
Not applicable.
7.8.4. Patient Follow-Up in Pragmatic Trials
Not applicable.


I5Q-MC-CGAR(a) Clinical Protocol
Page 29
LY2951742 
8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
All patients are free to withdraw from participation in this study at any time and for whatever 
reason, specified or unspecified, and without prejudice.
Patients who discontinue early from the study should complete study procedures listed in Event 
List F in the Schedule of Activities.
8.1.1. Temporary Discontinuation from Study Treatment
This protocol allows for temporary interruption of treatment, based on clinical symptoms of 
efficacy and response as judged by the investigator (Section 5.1). Dosing in this scenario may be 
re-initiated at the study investigator’s discretion.  If dosing is temporarily interrupted due to a 
potential safety concern, dosing may be re-initiated at the study investigator’s discretion 
following a discussion and agreement between the study investigator and Lilly Medical that re-
initiation of dosing is appropriate.
8.1.2. Discontinuation of Inadvertently Enrolled
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor CRP and the investigator to 
determine if the patient may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled patient to continue in the study with or without treatment with 
investigational product.
8.2.
Discontinuation from the Study
All patients may continue in the study and receive treatment with galcanezumab based on the 
study investigator’s judgment of clinical symptoms and response until the end of the study 
(described in Section 5.3). In addition, the study investigator should consider study 
discontinuation for an individual patient for the following:

Lack of benefit. The study physician should consider whether the patient is 
deriving benefit from galcanezumab.

Safety concerns, including evaluation of overall risk-benefit.

The investigator decides that the patient should be discontinued from the study for 
another reason.

Enrollment in any other clinical trial 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).


I5Q-MC-CGAR(a) Clinical Protocol
Page 30
LY2951742 

Subject decision.  The patient requests to be withdrawn from the study.
Discontinuation of the investigational product for abnormal liver tests should be considered by 
the investigator when a patient meets 1 of the following conditions after consultation with the 
Lilly designated medical monitor:

ALT or AST >8X ULN

ALT or AST >5X ULN for more than 2 weeks

ALT or AST >3X ULN and TBL level >2× ULN or prothrombin time 
>1.5X ULN

ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).
It is also recommended to consider discontinuation in a patient with ALP elevation which meets 
1 of the following criteria and is deemed to be of liver origin and drug related:

ALP >3X ULN

ALP >2.5X ULN and TBL >2X ULN

ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
Patients who discontinue from the study early will have end-of-therapy procedures performed as 
shown in Event List F in the Schedule of Activities (Table 2.1).
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she 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. Diligent attempts will be defined in the Protocol Operations Manual.


I5Q-MC-CGAR(a) Clinical Protocol
Page 31
LY2951742 
9.
Study Assessments and Procedures
Section 2 lists the Visit Flow Diagram and Schedule of Activities, with the study procedures and 
their timing.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 3 lists the hepatic monitoring tests for treatment-emergent abnormalities 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
The Patient Global Impression of Improvement (PGI-I) requests patients to mark the box that 
best describes your cluster headache condition since you started taking this medicine.  The 
options in the displayed boxes are represented on a seven-point scale, with 1=very much better 
and 7=very much worse (Guy 1976).
9.1.1. Appropriateness of Assessments
All efficacy and safety assessments have been well documented and are generally regarded as
reliable, accurate, and relevant in this patient population.
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.
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.
After the informed consent form (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 any change in the condition(s) and any new conditions as AEs. Investigators should 


I5Q-MC-CGAR(a) Clinical Protocol
Page 32
LY2951742 
record their assessment of the potential relatedness of each AE to protocol procedure, 
investigational product, via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to investigational product, study device, or a study procedure, taking into
account the disease, concomitant treatment or pathologies.
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
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 discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason:  important medical 
events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious, based upon appropriate medical judgment.

when a condition related to the disposable manual 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.
Although all AEs occurring after signing the ICF are recorded in the eCRF, SAE reporting 
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, it needs to be 
reported ONLY 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.


I5Q-MC-CGAR(a) Clinical Protocol
Page 33
LY2951742 
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.  
Pregnancy cases should be reported up to 5 months after last investigational product
administration.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject 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.
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 Commission Clinical Trial Directive 2001/20/EC
(United States Government Publishing Office [WWW]; European Commission [WWW]) 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 recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
9.2.1.2.
Adverse Event Monitoring with the Columbia-Suicide Severity Rating 
Scale, Self-Harm Supplement Form, and Self-Harm Follow-up Form
The C-SSRS and SHSF will be administered to assess and evaluate patients for suicide-related 
events (behavior and/or ideation) at every scheduled and unscheduled office visit as specified in 
the Schedule of Activities (Table 2.1).  Before administering the C-SSRS (Posner et al. 2011), 
study site personnel will question the patient about any change in the pre-existing condition(s) 
and the occurrence and nature of any AEs.  Nonserious AEs obtained through the questionnaire 
are recorded and analyzed separately.  Only serious AEs and AEs leading to discontinuation 
elicited through the C-SSRS are to be recorded as AEs via eCRF. Serious adverse events must 
be reported to Lilly or its designee within 24 hours as SAEs.  The SHSF captures the number of 
discrete events of suicidal behavior, possible suicidal behavior, or nonsuicidal self-injurious 
behavior recorded in the C-SSRS and must be completed at every visit.  Additionally, the SHFU 
will be completed at any visit, including screening/baseline visits, when a suicidal or nonsuicidal 
self-injurious behavior is identified.  At any time during the study, if a patient is considered to be 
at significant risk for suicide by the investigator, prompt referral of the patient to a mental health 
professional should be considered.
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 to 
facilitate process and product improvements.


I5Q-MC-CGAR(a) Clinical Protocol
Page 34
LY2951742 
Clinical staff must report a product complaint to the sponsor if a product quality issue is noted.  
Timeline expectations and instructions on how to report a product quality complaint are located 
on the provided study specific product complaint form.  For an SAE attributable to a product 
quality issue or defect, the complaint must be reported within the same timeframe as the SAE.
9.3.
Treatment of Overdose
Data not available.
9.4.
Safety
9.4.1. Electrocardiograms
For each patient, 12-lead digital ECGs will be collected according to the Schedule of Activities
(Table 2.1) as single ECGs for overread.  Patients must be supine for approximately 5 to 10 
minutes before ECG collection and remain supine but awake during ECG collection.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon after the time of ECG collection as possible, and ideally while the 
patient is still present, to determine whether the subject meets entry criteria and for immediate 
subject management, should any clinically relevant findings be identified. Electrocardiograms 
may be obtained at additional times, when deemed clinically necessary.
Electrocardiograms will have a central overread.  The investigator (or qualified designee) must 
document his/her review of the ECG printed at the time of evaluation, the final overread ECG 
report issued by the central ECG laboratory, and any alert reports.
9.4.2. Vital Signs
Blood pressure and pulse will be collected in triplicate according to the Schedule of Activities (
Table 2.1) and at unscheduled office visits.  All sites will be provided with an automated blood 
pressure machine with several cuff sizes.  The following guidelines will be used by investigative 
sites when measuring vital signs:

Blood pressure and pulse must be measured before any blood draws.

Blood pressure will be measured in sitting position with both feet resting on the 
floor after the patient has rested for at least 5 minutes.

Blood pressure will be measured with a cuff that is appropriate to the size of the 
patient.

Use the same arm for blood pressure collection throughout the study.

Arm with cuff must be supported at approximately the heart level.

Three sitting blood pressures and pulse measurements will be collected at 
approximately 30 to 60 second intervals.


I5Q-MC-CGAR(a) Clinical Protocol
Page 35
LY2951742 
9.4.3. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities Table 2.1). 
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.
9.4.4. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly 
CRP/clinical research scientist (CRS) will, as is appropriate, consult with the functionally 
independent Global Patient Safety therapeutic area physician or clinical scientist, and 
periodically review:

trends in safety data

laboratory analytes

AEs including monitoring of injection site reactions, allergic reactions, and 
infections
If a study patient/subject experiences elevated ALT 3× ULN, ALP 2× ULN or elevated 
TBL 2× ULN, clinical and laboratory monitoring should be initiated by the investigator.  
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory 
test abnormalities.  To ensure patient/subject safety and comply with regulatory guidance, the 
investigator is to consult with the Lilly designated medical monitor regarding collection of 
specific recommended clinical information and follow-up laboratory tests (Appendix 3).
9.4.5. Samples for Immunogenicity Research
Where local regulations and ethical review boards (ERB) allow, blood samples for 
immunogenicity testing will be collected to determine antibody production against galcanezumab
as specified in the Schedule of Activities (Table 2.1). Immunogenicity will be assessed by a 
validated assay designed to detect anti-drug antibody (ADAs) in the presence of the 
investigational product.  Antibodies may be further characterized and/or evaluated for their 
ability to neutralize the activity of the investigational product. 
Anti-drug antibody sampling will be initiated immediately prior to first patient dosing with 
galcanezumab (baseline).  Immunogenicity samples must be collected prior to dose 
administration if the visit is a dosing visit, and the timing of all samples will be recorded.
Samples will also be drawn in the event of early termination or as needed given any safety 
concerns judged to potentially immunologically mediated.


I5Q-MC-CGAR(a) Clinical Protocol
Page 36
LY2951742 
Samples
Samples will be drawn at Month 0 (first dose), Month 1, Month 6, and then every 6 months, 
thereafter; prior to dosing unless dosing is temporarily halted due to a clinical efficacy response.  
When dosing is temporarily halted due to a clinical efficacy response, an immunogenicity sample 
is scheduled for 1 month after the last dose of galcanezumab.  When dosing is resumed, an 
immunogenicity sample is drawn prior to dosing (Section 2, Schedule of Activities).  
Additionally, at study termination samples will be drawn approximately 1 month after the last 
dose of galcanezumab.
Samples will be retained for a maximum of 15 years after the last patient visit for the study, or 
for a shorter period if regulations and ERBs impose shorter time limits, at a facility selected by 
Lilly.  The duration allows the sponsor to respond to future regulatory requests related to the 
investigational product.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities Table 2.1), venous blood samples 
of approximately 3 mL each will be collected to determine the serum concentrations of 
galcanezumab.
A maximum of 3 samples per patient may be collected at additional time points during the study 
if warranted and agreed upon between both the investigator and sponsor.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  The actual date and 
time of each sampling will be recorded.
Bioanalytical samples collected to measure investigational product concentration will be retained 
for a maximum of 1 year following last patient visit for the study.
A validated assay will be used to determine galcanezumab concentrations.  Samples will be 
analyzed at a laboratory approved by the sponsor.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics and Genetics
Not applicable.
9.8.
Biomarkers
There are no biomarkers to be collected.
9.9.
Health Economics
The self-reported questionnaires will be administered according to the Schedule of Activities
(Table 2.1) in countries where the questionnaires have been translated into the native language of 
the region and linguistically validated.


I5Q-MC-CGAR(a) Clinical Protocol
Page 37
LY2951742 
European Quality of Life Questionnaire 5-Dimensions 5-Levels (EQ-5D-5L) (EuroQoL 
Group): A generic, multidimensional, health-related, quality-of-life instrument that contains 
2 parts: a health status profile and a VAS to rate global health-related quality of life. The profile 
allows patients to rate their health state on that day within 5 domains, including: mobility, self-
care, usual activities, pain/discomfort, and anxiety/depression (Brooks 1996; Herdman et al.
2011; Stafford et al. 2012).  A single score between 1 and 5 is generated for each domain with all
5 domains being mapped to a single index through an algorithm (Van Reenen and Janssen 2015).  
The index ranges between 0 and 1 with the higher score indicating a better health state perceived 
by the patient.  The VAS provides an overall patient rating of health status on that day, with a
range from 0 (i.e., “worst imaginable health state”) to 100 (i.e., “best imaginable health state”) 
serving as anchors for the patient’s numeric rating on the hash-marked, vertical VAS.
The EQ-5D-5L and cluster headache status data (Section 9.10) will be used to characterize 
changes in the health status of patient groups. The PGI-I, and other patient characteristics or 
clinical information may also be used to define specific patient groups associated with 
EQ-5D-5L outcomes. 
9.10. Cluster Headache Attack Assessments
The cluster headache status questions will collect information on the following:  if a patient is 
currently in a bout, the duration of the current bout or time since the last bout; and questions 
related to attacks that occurred over a 24-hour period (i.e., yesterday from midnight to midnight).  
Patients will be asked to record the number of cluster headache attacks during that time period, 
information regarding abortive medication use, cluster headache attack duration, and cluster 
headache attack pain severity will also be recorded.  Pain severity will be rated using a 5-point 
pain scale, where 0=no pain, 1=mild pain, 2=moderate pain, 3=severe pain, and 4=very severe 
pain.  Patients should record all cluster attacks regardless of attack duration.


I5Q-MC-CGAR(a) Clinical Protocol
Page 38
LY2951742 
10. Statistical Considerations
10.1. Sample Size Determination
The sample size for this study is not based on statistical or power considerations.  This is an 
open-label safety study for patients who previously enrolled in and completed Study CGAL or 
Study CGAM.  Therefore, the sample size is determined by the number of patients completing 
Studies CGAL and CGAM who choose to enroll in this study.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Evaluable
All enrolled patients who take at least 1 dose of investigational product.
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) document.
Efficacy and safety analyses will be conducted on the evaluable analysis set.  The evaluable 
analysis set includes all enrolled patients receiving at least 1 dose of the investigational product.
Baseline will be the time prior to receiving the first dose in this study.  Additional baselines may 
be further outlined in the SAP along with details related to missing data.
Safety and efficacy analyses will be evaluated based on a 2-sided significance level of 0.05 
unless otherwise stated.  The 95% confidence intervals (CI) for the change from baseline will be 
presented.  There will be no adjustments for multiplicity.
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 other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP or clinical study report (CSR).  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
10.3.2. Treatment Analyses
10.3.2.1. Patient Disposition
All patients who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported.  If known, a reason for their discontinuation will be 
given.


I5Q-MC-CGAR(a) Clinical Protocol
Page 39
LY2951742 
10.3.2.2. Patient Characteristics
The following information will be recorded at baseline and will be summarized for all enrolled 
patients.

Demographics (age, gender, race, ethnicity, height, weight, body mass index [BMI]); 
Note:  Age, gender, race, and ethnicity will be based upon the information from the 
parent trial.

Baseline disease characteristic.
o
Number of cluster headache attacks yesterday
o
Mean pain severity of cluster headache attacks yesterday
o
Mean duration of cluster headache attacks yesterday
o
Was abortive treatment used

Medical history and pre-existing conditions
10.3.2.3. Concomitant Therapy
The proportion of patients who receive concomitant medication will be summarized.
10.3.3. Efficacy Analyses
The proportion and exact 95% CI of patients reporting a score of 1 (“very much better”) or 
2 (“much better”) on the PGI-I 1 month after receiving their first dose will be reported.
Additional analysis of the PGI-I will be included in the SAP.
10.3.4. Safety Analyses
The safety and tolerability of treatment will be summarized by the following:

AEs
o
TEAEs

By preferred term (PT)

By system organ class (SOC)

By maximum severity

By outcome

Considered to be related to treatment by investigator
o
SAEs
o
AEs leading to discontinuation

Suicidal ideation and behaviors assessed by solicited questioning using the C-SSRS

Vital signs and weight

ECGs

Laboratory measurements
Unless specified otherwise, the categorical safety analyses will include both scheduled and 
unscheduled visits.
Treatment-emergent adverse events are defined as the reported AEs that first occurred or 
worsened during the post-baseline phase compared with the baseline phase.  For each TEAE, the 
severity level of the event (mild, moderate, or severe) will be determined by patient or physician 


I5Q-MC-CGAR(a) Clinical Protocol
Page 40
LY2951742 
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 post-baseline phase.  For each patient and TEAE, the 
maximum severity for the MedDRA level being displayed (PT, High level Term, or SOC) is the 
maximum post-baseline severity observed from all associated LLTs mapping to that MedDRA 
level.
For events that are gender-specific, the denominator and computation of the percentage will 
include only patients from the given gender.
Suicidal ideation, suicidal behavior, and non-suicidal self-injurious behavior based on the 
C-SSRS will be summarized.  For each of the following events, the number and percentage of 
patients with the event will be enumerated: completed suicide, non-fatal suicide attempt, 
interrupted attempt, aborted attempt, preparatory acts or behavior, active suicidal ideation with 
specific plan and intent, active suicidal ideation with some intent to act without specific plan, 
active suicidal ideation with any methods (not planned) without intent to act, nonspecific active 
suicidal thoughts, wish to be dead, and non-suicidal self-injurious behavior.  In addition, the 
number and percentage of patients who experienced at least 1 of the composite measures during 
SP II will be presented.  These include suicidal acts (completed suicide and nonfatal suicidal 
attempts), suicidal behavior (suicidal acts, interrupted attempts, aborted attempts, and 
preparatory acts or behavior), treatment-emergent suicidal ideation or treatment-emergent 
suicidal behavior.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Galcanezumab concentrations will be illustrated graphically and summarized descriptively.  If 
warranted and based on availability of data, the exposure-response relationship of serum 
galcanezumab concentrations to efficacy endpoints and/or safety endpoints may be explored.
Patient and healthy subject data from other clinical studies evaluating galcanezumab may be 
combined with data from this study to support additional analyses.  Such analyses may be 
reported separately.
10.3.6. Other Analyses
10.3.6.1. Health Economics
Each time point where the EQ-5D-5L survey is administered per the Schedule of Activities
(Table 2.1), the 5 domain items (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression) will be summarized as follows:

The sample size (n), mean, standard deviation, median, minimum, and maximum values 
will be reported.

Proportions within each of the categorical outcomes for the 5 domains


I5Q-MC-CGAR(a) Clinical Protocol
Page 41
LY2951742 

In addition, the percentage of patients with ‘problems’ (combined levels 2 through 5) and 
the percentage with ‘no problems’ (level 1) with be reported.
Each time point where the EQ-5D-5L survey is administered per the Schedule of Activities
(Table 2.1), the single index score (computed using the algorithm) and the VAS score will be 
summarized as follows:
The sample size (n), mean, standard deviation, median, minimum, and maximum values will be 
reported.  Changes from the start of treatment (first dose) to the stopping of treatment, and other 
time points when the EQ-5D-5L are collected, will also be analyzed; clinical variables and 
country effects will be considered.
10.3.7. Immunogenicity Analyses
Refer to the SAP for details.
10.3.8. Interim Analyses
Interim analyses may occur during the course of the study because of regulatory submission and  
as required for the evidence dossier for healthcare technology assessment bodies.  Any interim 
analysis will be documented including timing and data included.


I5Q-MC-CGAR(a) Clinical Protocol
Page 42
LY2951742 
11.
References
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37(1):53-72.
Edvinsson L, Goadsby PJ. Neuropeptides in migraine and cluster headache. Cephalalgia. 
1994;14(5):320-327.
European Commission. Clinical Trial Directive 2001/20/EC. DIRECTIVE 2001/20/EC OF THE 
EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States 
relating to the implementation of good clinical practice in the conduct of clinical trials on 
medicinal products for human use. 2001. Available at: 
http://ec.europa.eu/health/files/eudralex/vol-1/dir_2001_20/dir_2001_20_en.pdf. Accessed 
February 18, 2016.
Fanciullacci M, Alessandri M, Figini M, Geppetti P, Michelacci S. Increase in plasma calcitonin 
gene-related peptide from the extracerebral circulation during nitroglycerine-induced cluster 
headache attack. Pain. 1995;60(2):119-123.
Fanciullacci M, Alessandri M, Sicuteri R, Marabini S. Responsiveness of the trigeminovascular 
system to nitroglycerine in cluster headache patients. Brain. 1997;120(2):283-288.
Guy W. ECDEU assessment manual for psychopharmacology, revised 1976. Rockville, MD: 
National Institute of Mental Health, Psychopharmacology Research Branch. p 217-222. 
Available at: https://archive.org/details/ecdeuassessmentm1933guyw. Accessed January 5, 
2016.
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development 
and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20(10):1727-1736.
[ICHD-3] Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 
2013;33(9):629-808.
McCarthy PW, Lawson SN. Cell type and conduction velocity of rat primary sensory neurons 
with calcitonin gene-related peptide-like immunoreactivity. Neuroscience. 1990;34(3):623-
632.
Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin 
GA, Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial 
validity and internal consistency findings from three multisite studies with adolescents and 
adults. Am J Psychiatry. 2011;168(12):1266-1277.
Stafford MR, Hareendran A, Ng-Mak DS, Insinga RP, Xu R, Stull DE. EQ-5D™-derived utility 
values for different levels of migraine severity from a UK sample of migraineurs. Health Qual 
Life Outcomes. 2012;10:65.
Torelli P, Manzoni GC. Pain and behaviour in cluster headache. A prospective study and review 
of the literature. Funct Neurol. 2003;18(4):205-210.
United States Government Publishing Office. Electronic Code of Federal Regulations US 21 
CFR 312.32: Title 21 - Food and Drugs, Chapter I – Food and Drug Administration, 


I5Q-MC-CGAR(a) Clinical Protocol
Page 43
LY2951742 
Department of Health and Human Services, SubChapter D – Drugs for Human Use, 312 –
Investigational New Drug Application, Subpart B – Investigational New Drug Application 
(IND). 312.32 – IND safety reporting. Available at: http://www.ecfr.gov/cgi-bin/text-
idx?SID=36d454d0ed489a7c43698e492957c9c6&mc=true&node=se21.5.312_132&rgn=div8.
Accessed January 11, 2016.
van Reenen M, Janssen B. EQ-5D-5L User Guide: Basic information on how to use the EQ-5D-
5L instrument, version 2.1. 2015. Available at: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
5L_UserGuide_2015.pdf. Accessed January 18, 2016.


I5Q-MC-CGAR(a) Clinical Protocol
Page 44
LY2951742 
12.
Appendices


I5Q-MC-CGAR(a) Clinical Protocol
Page 45
LY2951742 
Appendix 1. Abbreviations and Definitions
Term
Definition
ADA
anti-drug antibody
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 AE 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.
ALT
alanine aminotransferase
ALP
alkaline phosphatase
ART-01
I5Q-MC-ART1
AST
aspartate aminotransferase
AV
atrioventricular
BMI
body mass index
BUN
blood urea nitrogen
C-SSRS
Columbia-Suicide Severity Rating Scale
CGAB
I5Q-MC-CGAB
CGAL
I5Q-MC-CGAL
CGAM
I5Q-MC-CGAM
CGAR
I5Q-MC-CGAR
cGMP
current good manufacturing practice
CGRP
calcitonin gene-related peptide
CI
confidence interval
CIDBF
capsaicin-induced dermal blood flow
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.


I5Q-MC-CGAR(a) Clinical Protocol
Page 46
LY2951742 
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician or other medical officer.
CRS
clinical research scientist
CSR
clinical study report
ECG
electrocardiogram
eCRF
electronic case report form
enroll
The act of assigning a patient to a treatment. Patients who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Patients entered into a trial are those who sign the ICF directly or through their legally 
acceptable representatives.
EQ-VAS
European Quality Visual Analogue Scale
EQ-5D-5L
European quality 5-dimensions 5-levels
ERB
Ethical Review Board
EuroQoL
European quality of life
FSH
follicle stimulating hormone
GCP
good clinical practice
HbA1C
hemoglobin A1C
IB
Investigator’s Brochure
ICF
informed consent form
ICHD-3
International Classification of Headache Disorders, Third edition, beta version
ICH
International Conference on Harmonisation
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.
Lilly
Eli Lilly and Company
LLT
lowest level term
LSD
Lysergic acid diethylamide


I5Q-MC-CGAR(a) Clinical Protocol
Page 47
LY2951742 
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
PGI-I
Patient Global Impression of Improvement
PK/PD
pharmacokinetics/pharmacodynamics
PT
preferred term
Q2W
every two weeks
QT
QT interval
QTc
corrected QT interval
QTcB
Corrected QT interval (Bazett’s Formula)
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
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. 
SHSF
Self-Harm Supplement Form
SHFU
Self-Harm Follow-up Form
SOC
system organ class
SP
study phase
SP I
screening phase
SP II
open-label treatment phase
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, which and does not necessarily have to have a causal 
relationship with this treatment.
UA
unstable angina
ULN
upper limit of normal
UDS
urine drug screen


I5Q-MC-CGAR(a) Clinical Protocol
Page 48
LY2951742 
V
visit
VAS
visual analogue scale


I5Q-MC-CGAR(a) Clinical Protocol
Page 49
LY2951742 
Appendix 2. Clinical Laboratory Tests
Clinical Laboratory Tests
Hematology:
Clinical Chemistry:
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
HbA1C
Calcium
Glucose
Urinalysis:
Albumin
Specific gravity
Creatine kinase (CK)
pH
Total Cholesterol
Protein
Glucose
Ketones
Other 
Blood
Urine leukocyte esterase
PK Sample (galcanezumab serum concentration 
determination)
Immunogenicity
Urine Drug Screena
Pregnancy Testa (females only)
Serum pregnancy or FSH
Urine pregnancy testing
Abbreviations: FSH = follicle-stimulating hormone; PK = pharmacokinetic; RBC = red blood cells; WBC = white 
blood cells.
a
May be repeated during the study at the discretion of the investigator.


I5Q-MC-CGAR(a) Clinical Protocol
Page 50
LY2951742 
Appendix 3. 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.
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
Alkaline phosphatase isoenzymesa
GGT
Anti-Actin antibodya
CPK
Anti-smooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
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.


I5Q-MC-CGAR(a) Clinical Protocol
Page 51
LY2951742 
Appendix 4. Study Governance Considerations
Appendix 4.1.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 4.1.1.
Informed Consent
The investigator is responsible for ensuring:

that the patient understands the potential risks and benefits of participating in 
the study.

that informed consent is given by each patient.  This includes obtaining the 
appropriate signatures and dates on the 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 trial.
Appendix 4.1.2.
Ethical Review
The investigator must give assurance that the ERB was properly constituted and convened as 
required by International Conference 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 site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
Appendix 4.1.3.
Regulatory Considerations
This study will be conducted in accordance with:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations


I5Q-MC-CGAR(a) Clinical Protocol
Page 52
LY2951742 
Some of the obligations of the sponsor will be assigned to a third-party.
Appendix 4.1.4.
Investigator Information
Licensed physicians with a specialty including, but not limited to, neurology and headache 
specialists will participate as investigators in this clinical trial.
Appendix 4.1.5.
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 4.1.6.
Final Report Signature
The 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.
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 4.2.
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

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.


I5Q-MC-CGAR(a) Clinical Protocol
Page 53
LY2951742 
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 4.2.1.
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.
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.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 4.3.
Study and Site Closure
Appendix 4.3.1.
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 4.3.2.
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.


I5Q-MC-CGAR(a) Clinical Protocol
Page 54
LY2951742 
Appendix 5.
Protocol Amendment Summary:  I5Q-MC-
CGAR(a)
Overview
Protocol I5Q-MC-CGAR(a), a Phase 3b Multicenter, Single-Arm, Open Label Safety Study of 
LY2951742 (galcanezumab) in Patients with Episodic or Chronic Cluster Headache, has been 
amended.  The new protocol is indicated by amendment (a) and will be used to conduct the study 
in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Revised Exclusion Criterion 14a to allow for medical judgment in determining exclusion 
from Study CGAR based on abnormal ECG findings in Study CGAL or Study CGAM.

Revised Exclusion Criterion 14e because intracranial or carotid aneurysm, intracranial 
hemorrhage, and stroke are cardiovascular-related conditions, whereas intracranial tumor 
and significant head trauma are not cardiovascular related.  Patients with either of the 
non-cardiovascular-related conditions mentioned here may be enrolled in the clinical trial 
if upon discussion with Lilly Medical it is judged not to indicate a medical problem that 
would preclude study participation (see Exclusion Criterion 15d).  This revision aligns 
Study CGAR with Study CGAL and Study CGAM.

Revised Exclusion Criterion 14f to allow for medical judgment in determining exclusion 
from CGAR based on blood pressure readings in Study CGAL or Study CGAM.  This 
revision provides study investigators with the flexibility to employ medical judgment in 
determining exclusion of patients with inconsistent blood pressure readings during 
participation in Study CGAL and Study CGAM.

Revised Exclusion Criterion 15c to allow patients who fail eligibility due to an elevation 
of ≥2X ULN for ALT, or ≥1.5X ULN TBL or ALP to be retested.  The patient’s results 
must be discussed and judged not clinically significant by Lilly Medical prior to 
enrollment.  This revision aligns Study CGAR with Study CGAL and Study CGAM.

Added Exclusion Criterion 15d to allow for patients with a history of intracranial tumor 
or head trauma  to be enrolled in Study CGAR based on medical discretion.  This 
addition aligns Study CGAR with Study CGAL and Study CGAM.

Section 6.4 was revised to allow for rescreening of patients who fail eligibility due to a 
positive UDS.

Revised protocol text in Section 3.1, Section 5.1, and Section 8.1 to clarify study 
discontinuation for those patients whose dosing is temporarily interrupted for potential 
safety concerns.  For these patients, the site investigator in consultation with Lilly 
Medical will determine if dosing can resume for the patient whose potential safety
concern is either ruled out, resolved, or otherwise treated.  This revision will allow 
patients who experience a temporary or unconfirmed medical condition and would 
otherwise be discontinued from Study CGAR to continue to receive treatment as long as 


I5Q-MC-CGAR(a) Clinical Protocol
Page 55
LY2951742 
the site investigator, in consultation with Lilly Medical, determines that it is appropriate 
to do so.

Minor editorial changes to correct errors or clarify content were made throughout the 
protocol.


I5Q-MC-CGAR(a) Clinical Protocol
Page 56
LY2951742 
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
3.1 Study Rationale
Study CGAR is a Phase 3b study to assess the long-term safety and tolerability of galcanezumab
300 mg in patients with episodic or chronic cluster headache who have completed one of the 
Phase 3 double-blind, placebo-controlled studies, CGAL or CGAM.
Study CGAR will implement a dosing strategy to more closely approximate what may occur in 
clinical practice.  For each patient, the study investigator will determine whether or not to dose 
galcanezumab 300 mg at each monthly interval based on clinical symptoms and response.  
Dosing will be no more frequent than once per month, and the investigator may choose to not 
dose galcanezumab for 1 or more months at their clinical discretion based on clinical efficacy.  
As such, some patients may receive monthly long-term treatment with galcanezumab for a period 
of months or years during the study, while others may have 1 or more months of galcanezumab 
dose-free intervals based on the investigator’s judgment of clinical efficacy.  If, however, the 
investigator stops monthly dosing due to safety concerns, dosing with galcanezumab should not 
be resumed.
5.1 Overall Design
Study Phase II:  SP II is the single-arm open-label treatment phase during which patients can 
receive galcanezumab 300 mg administered SC up to once a month.  If a patient meets all 
eligibility requirements, a urine pregnancy screen will be conducted at the first dosing visit, prior 
to dosing to confirm that a female patient is not pregnant before administering investigational 
product.  Following the first dose of galcanezumab, the patient should remain in the office for 
30 minutes of observation.  The site will have a scheduled telephone visit (V23) with the patient 
approximately 1 week after the first investigational product administration to collect 
spontaneously reported AEs.
Every month, the decision whether to administer a monthly dose will be based upon the study 
investigator’s judgment, which is not limited to, but includes assessment of the patient’s clinical 
symptoms and response as follows:

Dosing is up to once monthly; more frequent dosing is not allowed.  The full 300 mg 
dose is to be administered, changing the dose amount is not allowed. 

If the patient remits and dosing is halted, the patient may remain in the study, but they 
should have an office visit 1 month after the last dose to complete the procedures listed in 
Event List F (Table 2.1).  Dosing in this scenario may be re-initiated at the study 
investigator’s discretion.


I5Q-MC-CGAR(a) Clinical Protocol
Page 57
LY2951742 

Monthly telephone visits should be completed for patients who are not being dosed, but 
remain in the study (e.g., in remission).

Dosing may be re-initiated at the study investigator’s discretion, as long as dosing was 
not halted due to a safety concern, and should be based upon the patient experiencing a 
cluster headache attack or the anticipated onset of a cluster headache period/bout, based 
on the patient’s history (for example, the anticipated onset of a new cluster period in the 
spring based on a patient’s history of spring-onset cluster periods).  If dosing is 
temporarily interrupted due to a potential safety concern, dosing may be re-initiated at the 
study investigator’s discretion following a discussion and agreement between the study 
investigator and Lilly Medical that re-initiation of dosing is appropriate.
o
At the office visit prior to re-initiation of dosing the following procedures:  
ECG, immunogenicity, pharmacokinetics (PK), hematology, clinical chemistry, 
HbA1c and urine pregnancy are to be collected.  The urine pregnancy must be 
negative and the ECG should be evaluated for safety prior to dosing.

If dosing is halted for a  safety reason, the patient should be discontinued (Section 
8.2).
6.1 Inclusion Criteria
1. Patients who participated in and completed either Study CGAL or Study CGAM.  A study
completer is defined as follows:
a.
Study CGAL:  a patient who has completed the double-blind treatment and post-
treatment follow-up phases.
b. Study CGAM:  a patient who has completed the double-blind treatment, open-label 
extension and post-treatment follow-up phases.  However, if a patient entered Study 
CGAM prior to Study CGAR being open for enrollment, they will be considered a 
completer if they completed the double-blind treatment and post-treatment follow-up 
phases (e.g., opted not to participate in the open-label extension).
6.2 Exclusion Criteria 
8. Use of therapeutic antibodies (except galcanezumab) during the course of the study (for 
example, adalimumab, infliximab, trastuzumab, bevacizumab, etc.).  Prior use of other 
therapeutic antibodies is allowed if an adequate washout has occurred (≥5 half-lives) prior 
to V2.
14. Any of the following cardiovascular-related conditions are exclusionary:
a.
Since enrolling in Study CGAL or Study CGAM or prior to V2 (enrollment), have 
ECGs showing acute abnormalities of:
i. evidence of delayed ventricular repolarization including but not limited to a 
corrected QT (Fridericia’s QT interval [QTcF]) interval >470 msec for women 
and >450 for men, and/or


I5Q-MC-CGAR(a) Clinical Protocol
Page 58
LY2951742 
ii. evidence of atrioventricular (AV) depolarization of PR>220, or conduction delay 
of QRS>120, and/or
iii. evidence of ischemia or any of the qualitative findings indicative of ST or J-point 
elevation, excluding those findings consistent with early repolarization (non-
ischemic).
NOTE:  Patients who meet 1 of the 14(a) ECG criteria during Study CGAL or Study 
CGAM may enroll in Study CGAR if the study investigator deems the finding not 
clinically significant.
b. History of myocardial infarction (MI), unstable angina (UA), percutaneous coronary 
intervention, coronary artery bypass graft, deep vein thrombosis/pulmonary embolism 
since enrolling in Study CGAL or Study CGAM and prior to V2 of Study CGAR, or 
have planned cardiovascular surgery or percutaneous coronary angioplasty or surgery 
for peripheral arterial disease.
c.
Any lifetime history of vasospastic angina or stroke, or history of emergency room 
visit for chest pain in which an ischemic or cardiac event was not ruled out since 
enrolling in Study CGAL or Study CGAM and prior to V2 of Study CGAR.
d. Clinical evidence of peripheral vascular disease (e.g., Buerger’s Disease) or a 
diagnosis of Raynaud’s Disease or Raynaud’s Phenomenon.
e.
Have any history of intracranial or carotid aneurysm, intracranial hemorrhage, or
stroke.  , intracranial tumors or significant head trauma.
f.
Have uncontrolled high blood pressure characterized by systolic blood pressure 
>160 mmHg or diastolic blood pressure >100 mmHg on 2 or more blood pressure 
assessments prior to V2 of Study CGAR.
NOTE:  Patients who meet the 14(f) blood pressure criteria during Study CGAL or 
Study CGAM may enroll in Study CGAR if the study investigator deems the finding 
not clinically significant.
15. Any of the following medical conditions are exclusionary:
a.
Have a lifetime history of seizures (except for childhood febrile seizures).
b. Have a history or presence of any other medical illness including but not limited to 
any cardiovascular, hepatic, respiratory, hematological, endocrine, psychiatric or 
neurological disease, or any clinically significant laboratory abnormality, that in the 
judgment of the investigator indicates a medical problem that would preclude study 
participation.
c.
Prior to V2, patients who have an elevation of ≥2× the upper limit of normal (ULN)
for alanine aminotransferase (ALT), or ≥1.5× ULN for total bilirubin (TBL) or 
alkaline phosphatase (ALP) may be retested.  The patient’s results must be discussed 
with  Lilly Medical and judged not clinically significant prior to enrollment.
NOTE:  Patients with TBL ≥1.5× ULN are not excluded if they meet all of the 
following criteria for Gilbert syndrome:


I5Q-MC-CGAR(a) Clinical Protocol
Page 59
LY2951742 
1. Bilirubin is predominantly indirect (unconjugated) at screening (direct 
bilirubin within normal limits)
2. Absence of liver disease
3. ALT, aspartate aminotransferase (AST), and ALP ≤1× ULN at screening
4. Hemoglobin not significantly decreased at screening
d. Patients with a history of an intracranial tumor or head trauma must be discussed and 
judged not to indicate a medical problem that would preclude study participation by 
Lilly Medical prior to enrollment.
6.4 Screen Failures
Exclusion Criteria 16(b):  If a patient fails eligibility due to a positive UDS, the patient may be 
considered for rescreen.
8.1.1 Temporary Discontinuation from Study Treatment
This protocol allows for temporary interruption of treatment, based on clinical symptoms of 
efficacy and response as judged by the investigator (Section 5.1).  Dosing in this scenario may be 
re-initiated at the study investigator’s discretion.  Temporary discontinuation of treatment due to 
safety concerns or AEs is not allowed; discontinuation of treatment due to safety concerns or 
AEs will be considered permanent discontinuation of treatment and the patient must not be 
subsequently re-started on investigational product (Section 8.2). If dosing is temporarily 
interrupted due to a potential safety concern, dosing may be re-initiated at the study 
investigator’s discretion following a discussion and agreement between the study investigator 
and Lilly Medical that re-initiation of dosing is appropriate.


Leo Document ID = 4f9bd8fd-7a4f-4a7c-bdbd-f7ae22950e0e
Approver: 
Approval Date & Time: 11-May-2017 20:13:36 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 15-May-2017 14:56:33 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan: I5Q-MC-CGAR (v3) 
 
 
Statistical Analysis Plan for Protocol I5Q-MC-CGAR: A Phase 3b 
Multicenter, Single-Arm, Open-Label Safety Study of LY2951742 in 
Patients with Episodic or Chronic Cluster Headache 
 
 
NCT02797951 
 
 
Approval Date: 02-Mar-2021 


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 1
LY2951742
1.
Statistical Analysis Plan for Protocol I5Q-MC-CGAR:  A 
Phase 3b Multicenter, Single-Arm, Open-Label Safety 
Study of LY2951742 in Patients with Episodic or Chronic 
Cluster Headache
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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)
Study CGAR is a Phase 3b multicenter, single-arm, open-label safety study of 
galcanezumab 300 mg in outpatients with episodic or chronic cluster headache who 
completed study I5Q-MC-CGAL or I5Q-MC-CGAM. The study has 2 study phases (SP): 
SP I (screening phase), and SP II (open-label treatment phase).  
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I5Q-MC-CGAR
Phase 3b
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:
12 July 2016
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly:
31 Jan 2018
Statistical Analysis Plan Version 3 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 02-Mar-2021 GMT


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 2
LY2951742
2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for Protocol I5Q-MC-CGAR:  A Phase 3b 
Multicenter, Single-Arm, Open-Label Safety Study of LY2951742 in 
Patients with Episodic or Chronic Cluster Headache ...........................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................5
4.
Study Objectives.................................................................................................................7
Primary Objective ..........................................................................................................7
Secondary Objectives.....................................................................................................7
Tertiary Objectives.........................................................................................................7
5.
A Priori Statistical Methods ................................................................................................8
Study Design..................................................................................................................8
Determination of Sample Size ........................................................................................8
Randomization and Treatment Assignment ....................................................................8
General Considerations ..................................................................................................8
Adjustments for Covariates ............................................................................................8
Handling of Dropouts or Missing Data...........................................................................9
Multicenter Studies ........................................................................................................9
Patient Disposition .........................................................................................................9
Important Protocol Deviations........................................................................................9
Patient Characteristics ....................................................................................................9
Treatment Exposure and Compliance ...........................................................................10
Concomitant Therapy...................................................................................................10
Efficacy Analyses ........................................................................................................10
Health Outcomes/Quality-of-Life Analyses..................................................................10
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................11
Safety Analyses............................................................................................................11
5.16.1.
Treatment-Emergent Adverse Events ...................................................................12
5.16.2.
Potential Hypersensitivity Events.........................................................................12
5.16.3.
Adverse Events Related to Injection Sites ............................................................13
5.16.4.
Upper Respiratory Tract Infections.......................................................................13
5.16.5.
Suicide-Related Thoughts and Behaviors .............................................................13
5.16.6.
Vital Signs and Weight ........................................................................................14
5.16.7.
Electrocardiogram Intervals and Heart Rate .........................................................16
5.16.8.
Laboratory Tests ..................................................................................................17
5.16.9.
Immunogenicity...................................................................................................17


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 3
LY2951742
5.16.9.1.
Definitions of Patient ADA Status ..................................................................18
5.16.9.2.
Immunogenicity Analyses to be Performed.....................................................18
Reports to Be Generated at Each Interim and Final Database Lock...............................18
5.17.1.
Report to Be Generated at Interim Database Locks...............................................18
5.17.2.
Report to Be Generated at Final Database Lock....................................................19
Clinical Trial Registry Analyses...................................................................................19
6.
Reference..........................................................................................................................20
7.
Appendices .......................................................................................................................21


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 4
LY2951742
Table of Contents
Table
Page
Table CGAR.5.1.Categorical Changes of Interest in Vital Signs and Weight.............................15
Table CGAR.5.2.Criteria for Treatment-Emergent Changes in ECG Intervals and Heart 
Rate...............................................................................................................16


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 5
LY2951742
3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved on 12 July 2016 prior to first patient 
visit. 
Statistical Analysis Plan Version 2 was approved prior to the database lock for the interim 
analysis supporting cluster headache indication submission. The overall changes and rationale 
for the changes incorporated in Version 2 are as follows:

LY2951742 was replaced by galcanezumab in the body of the SAP.

Analysis populations are updated.  Evaluable analysis set is renamed to GMB-treated 
population; continuous treatment exposure population set is removed. 

GMB-treated time and off-treatment time are defined, and the safety analyses will be 
performed during the GMB-treated time in addition to the whole open-label treatment 
phase including both GMB-treated time and off-treatment time.

The list of protocol deviations in Section 5.9 was moved to Appendix 1 with a complete 
list of important protocol deviations.

Safety analyses are reduced to summaries of AE overview, TEAE, SAE, and DCAE,
since detailed planned analyses of Study CGAR safety data are more thoroughly 
described in PSAP for cluster headache indication in the context of combining the safety 
data from the originating studies with the safety data from Study CGAR. 

Section 5.17.  Reports to Be Generated at Each Interim and Final Database Lock was 
added.

Other minor corrections, modifications, and clarifications were made.
Statistical Analysis Plan Version 3 was approved prior to the final study database lock.  The 
overall changes and rationale for the changes incorporated in Version 3 are as follows:

General formatting and grammatical edits were made to improve clarity.

The PGI-I analyses in Section 5.13 were updated to remove a graphical display; a tabular 
summary will be presented instead, without 95% confidence intervals.

The description of the EQ-5D-5L questionnaire was updated in Section 5.14 to provide 
additional details for the derivation of the health state index scores.  A description of the 
correlation analyses of EQ-5D-5L with PGI-I and cluster headache status was also added 
to meet the stated tertiary objectives. 

The following safety analysis descriptions were added in Section 5.16, to be consistent 
with the analysis approaches described in the SAPs for the other Emgality Phase 3 cluster 
headache studies:
o
Potential hypersensitivity events (Section 5.16.2)
o
AEs related to injection sites (Section 5.16.3)
o
Upper Respiratory Tract Infections (Section 5.16.4)
o
Suicide-related thoughts and behaviors (Section 5.16.5)
o
Vital signs and weight (Section 5.16.6)


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 6
LY2951742
o
Electrocardiogram Intervals and Heart Rate (Section 5.16.7)
o
Laboratory tests (Section 5.16.8) 
o
Immunogenicity (Section 5.16.9)

The data cutoff dates for the two interim database locks were added in Section 5.17.1 for 
the interim locks used to support the regulatory submission and safety update report, 
respectively.

The list of important protocol deviations in Appendix 1 were updated to align with the 
current version of the Trial Issue Management Plan (Version 12).


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 7
LY2951742
4.
Study Objectives
Primary Objective
The primary objective of this study is to evaluate the safety of open-label galcanezumab within 
the context of expected medical practice in eligible patients with episodic or chronic cluster 
headache. Safety will be assessed using treatment-emergent adverse events (TEAEs), serious 
adverse events (SAEs), as well as suicidal ideation and behaviors utilizing the Columbia-Suicide 
Severity Rating Scale (C-SSRS).
Secondary Objectives
Characterize the reasons for discontinuation and frequency of adverse events (AEs) of interest 
for galcanezumab. The AEs of interest are those related to injection sites, hypersensitivity 
events, and upper respiratory tract infections. 
Characterize the immunogenicity of galcanezumab.  The immunogenicity will be assessed by the 
assessment of anti-drug antibodies (ADA) to galcanezumab, their relationship with AEs, and 
neutralizing ADA to galcanezumab.
Tertiary Objectives
Evaluate the effectiveness of galcanezumab by the assessment of the proportion of patients 
reporting a score of 1 (“very much better”) or 2 (“much better”) on the Patient Global Impression 
of Improvement (PGI-I) 1 month after receiving their first dose.
Evaluate the effect of LY2951742 on health values by the analyses of the European Quality 5-
Dimensions 5-levels (EQ-5D-5L) on (1) health state index values; (2) each dimension of the 
descriptive system and dichotomized level responses; (3) European Quality Visual Analogue 
Scale (EQ-VAS) current health score; and (4) correlations with PGI-I, cluster headache status.


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 8
LY2951742
5.
A Priori Statistical Methods
Study Design
Determination of Sample Size
The sample size for this study is not based on statistical or power considerations.  This is an 
open-label safety study for patients who previously enrolled in and completed studies CGAL or 
CGAM.  Therefore, the sample size is determined by the number of patients completing studies 
CGAL and CGAM who choose to enroll in this study.
Randomization and Treatment Assignment
All patients will receive the same treatment:  galcanezumab 300 mg (GMB 300mg).  Every 
month, the decision whether to administer a monthly dose will be based upon the study 
investigator’s judgment.
General Considerations
General aspects of statistical analyses are described below.
Unless otherwise specified, analyses will be conducted in the GMB-treated population, which 
includes all patients who are enrolled and receive at least 1 dose of study drug in Study CGAR, 
and analyses will be presented with 1 treatment arm.  Safety analyses will be performed during 
the GMB-treated time and during the whole open-label treatment phase (SP II), which includes 
both GMB-treated time plus off-treatment time. GMB-treated time is composed of monthly 
dosing intervals, that is, the time from a GMB dose to the next monthly visit.  The time between 
the first monthly visit that a dose is not administered and the dosing re-initiation visit is counted 
as off-treatment time.  Baseline will be the time during SP I prior to receiving the first dose in 
this study.  For safety analyses during the open-label treatment phase, any time after the first 
dose of GMB 300 mg will be considered as postbaseline period no matter if it is during an on-
treatment or off-treatment month.  For safety analyses during the GMB-treated time, only events 
that occurred during the GMB-treated time will be considered as postbaseline values.
Statistical analysis of this study will be the responsibility of Lilly or its designee. SAS® software 
will be used to perform most or all statistical analyses.
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 other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP or clinical study report (CSR).  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.
Adjustments for Covariates
Statistical modeling of data using covariates is not anticipated in this study.  However, such 
modeling may be performed as post hoc analyses if deemed appropriate.


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 9
LY2951742
Handling of Dropouts or Missing Data
Last-observation-carried-forward (LOCF) will be used in handling of missing data when it is 
applicable.  For those patients who are lost to follow-up, or who drop out of the study, the 
analyses will include all data up to the point of their last data collection.
Multicenter Studies
Statistical modeling of data using country or site as covariates is not anticipated in this study.  
However, such modeling may be performed as post hoc analyses if deemed appropriate.
Patient Disposition
The number and percentage of GMB-treated patients who discontinue early will be tabulated 
along with reasons for discontinuation.
Patient allocation and reasons for discontinuation by investigator will also be listed.
Important Protocol Deviations
Summary and listing of subjects with important protocol deviations will be provided for the 
GMB-treated population. 
Section 7 (Appendix 1) lists the categories, subcategories, study specific terms of important 
protocol deviations, and source of identification.  Per study team’s discretion, for non-
programmable protocol deviation, additional categories and subcategories other than the ones in
Appendix 1 can always be added into the final nonprogrammable protocol deviations list as 
deemed necessary.
Patient Characteristics
The following patient characteristics at baseline will be summarized for all GMB-treated
patients:

Demographics (age, gender, race, ethnicity, height, weight, body mass index, country, 
region)
Note:  Age, gender, race, and ethnicity will be based upon the information from the 
parent trial.

Baseline disease characteristics:
o
number of cluster headache attacks yesterday
o
mean pain severity of cluster headache attacks yesterday
o
mean duration of cluster headache attacks yesterday
o
was abortive treatment used?
Pre-existing conditions will be summarized.  Pre-existing conditions are medical events ongoing 
at the time of informed consent.
Note:  The reference to yesterday defines a 24-hour period from midnight to midnight the day 
before the assessment date.


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 10
LY2951742
Treatment Exposure and Compliance
This open-label study dosing will be based upon the study investigator’s judgment and there will 
not be any formal computation of treatment compliance. Total number of monthly doses 
administered will be summarized for the GMB-treated population.  Treatment received will also 
be reported in an individual subject listing by providing the date, time, and the injection dose 
administered.  
Concomitant Therapy
The proportion of patients who receive concomitant medication will be summarized using the 
WHODRUG dictionary preferred term (PT) and will be presented in the order of decreasing 
frequency of usage.  If there are different PTs for salt forms of a preventive or abortive 
medication, these PTs will be combined for the medication in the presentation.  Concomitant 
therapies are those that started on or continued after the date of first dose of study medication. 
All records will be used in the above summary even if frequency, dose, or dates of use are 
missing. 
Efficacy Analyses
Descriptive summaries of the PGI-I, a 7-point scale, with 1=very much better and 7=very much
worse (Guy 1976) will be presented at each time point collected during postbaseline, as 
described in the schedule of activities.  It will be summarized as both a categorical and 
continuous variable. 
The proportion of patients reporting a score of 1 (“very much better”) or 2 (“much better”) on the 
PGI-I 1 month after receiving their first dose will be reported.  
Health Outcomes/Quality-of-Life Analyses
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” (The EuroQol Group 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). Answers to these 5 
dimensions define a patient’s health state.  Given a patient’s health state, the patient’s country-
specific health state index value can be obtained from the country-specific value set. 
A country-specific value set is derived from valuation research that aims to measure how health 
is valued by people in a country. The valuation research includes a representative sample of 
participants from the general population in that country.  In the valuation study participants are 
asked to value health by reviewing EQ-5D health states. The result from the valuation study is 
a value set for that country.  The value set is essentially a set of weights to each of the levels in 
each EQ-5D dimension. A high weight means that people in that country believe that such a 
score has a high impact on health-related quality of life. 


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 11
LY2951742
The health state index value is 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 UK population-based and US population-
based health state index values are calculated based on the value sets from 
https://euroqol.org/wp-content/uploads/2018/02/EQ-5D-5L_Crosswalk_Value_Sets.xls
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). 
Descriptive statistics (n, mean, standard deviation [SD], range, median, 25th and 75th percentiles, 
min, max) for EQ-5D-5L Health State Index overall score based on US and UK population, 
scores for each of the 5 EQ-5D-5L dimensions (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression), and EQ-5D-5L VAS current health score will be 
provided by visit. The number and percentage of patients with dichotomized responses 
(problems, no problems) for each of the 5 EQ-5D-5L dimensions will also be provided by visit. 
To assess the correlation of EQ-5D-5L Health State Index Scores and VAS current health score 
with PGI-I and cluster headache status, the following analyses will also be performed:

A correlation analysis between mean change from baseline in EQ-5D-5L with PGI-I at 
month 1, using Spearman’s rank correlation coefficient.

An Analysis of Variance (ANOVA) comparing mean change from baseline in EQ-5D-5L 
by cluster headache status (active or remission) at month 1 and month 6. 
Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
Bioanalytical and Pharmacokinetic/Pharmacodynamic (PK/PD) methods are not applicable to 
this SAP. An analysis of PK/PD data is not planned as part of this SAP but will be documented 
separately according to global PK/PD procedures.
Safety Analyses
For purposes of the cluster headache regulatory submission, analyses of Study CGAR safety data 
are more thoroughly assessed in the context of combining the safety data from the parent studies 
with the safety data from Study CGAR.  The planned integrated analyses are described in 
separate documents.  For the purpose of Study CGAR alone, the safety and tolerability of 
treatment will be summarized by the following:   

AEs
o
TEAEs

by PT

by PT nested within system organ class (SOC)
o
SAEs, by PT nested within SOC
o
AE leading to discontinuation, by PT nested within SOC
o
Potential hypersensitivity events


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 12
LY2951742
o
AEs related to injection sites

Suicide-related thoughts and behaviors

Vital signs and weight

ECGs

Laboratory measurements

Anti-drug antibodies (ADA) and neutralizing ADA (NAb)
Unless otherwise specified, safety analyses will be conducted for the GMB-treated population 
during GMB-treated time and GMB-treated time plus off-treatment time.  Categorical safety 
analyses will include both scheduled and unscheduled visits.
5.16.1. Treatment-Emergent Adverse Events 
Treatment-emergent AEs are defined as the reported AEs that first occurred or worsened during 
the postbaseline phase compared with baseline phase.  For events occurring on the day of first 
administration of study drug, the case report form collected flag will be used to determine 
whether the event was pre-treatment versus post-treatment. For each TEAE, the 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 events with a 
missing severity during the baseline period, it will be treated as “mild” in severity; for events 
with a missing severity during the postbaseline period, it will be treated as ‘severe” for TEAE 
computation. For each patient and TEAE, the maximum severity for the MedDRA level being 
displayed (PT, High Level Term, or SOC) is the maximum postbaseline severity observed from 
all associated LLTs mapping to that MedDRA level.  
For events that are male- or female-specific, the denominator and computation of the percentage 
will only include patients from that specific sex.
5.16.2. Potential Hypersensitivity Events
Potential hypersensitivity events will be defined using the following terms (standard MedDRA 
query [SMQ]):

broad and narrow terms in the “Anaphylactic reaction” SMQ (20000021) 

broad and narrow terms in the “Angioedema” SMQ (20000024) 

broad and narrow terms in the “Hypersensitivity” SMQ (20000214)
A listing of patients having an event identified from these analyses will be medically reviewed to 
determine if the terms identified represent events likely hypersensitivity in nature. Listings 
should include information on timing of event relative to latest dose of study drug 
administration, the event term from this query, other AEs for the patient and timing, any 
abnormal laboratory findings, concomitant medication, medical history and pre-existing 


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 13
LY2951742
conditions. Only those that are judged medically to be events likely hypersensitivity in nature 
will be included in the final summary.
The number and percentage of patients with likely hypersensitivity TEAEs will be summarized 
by treatment groups using MedDRA PT nested within the SMQ.  Events will be ordered by 
decreasing frequency within the SMQ.
5.16.3. Adverse Events Related to Injection Sites
Adverse events related to injection sites will be defined using terms from the MedDRA High 
Level Term “Injection site reactions.”
The number and percentage of patients with TEAEs related to injection sites will be summarized 
using MedDRA PT.  Events will be ordered by decreasing frequency of PT term.
5.16.4. Upper Respiratory Tract Infections
Upper respiratory tract infections will be defined using all the PTs from the 2 High Level Terms 
of “upper respiratory tract infections” and “upper respiratory tract infections NEC” as defined in 
MedDRA.
5.16.5. Suicide-Related Thoughts and Behaviors
Postbaseline suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal 
intent, based on the C-SSRS, will be summarized for the GMB-treated population during GMB-
treated time and GMB-treated time plus post-treatment time.  In particular, for each of the 
following events, the number and percent of patients with the event will be enumerated:  
completed suicide, nonfatal suicide attempt, interrupted attempt, aborted attempt, preparatory 
acts or behavior, active suicidal ideation with specific plan and intent, active suicidal ideation 
with some intent to act without specific plan, active suicidal ideation with any methods (no plan) 
without intent to act, nonspecific active suicidal thoughts, wish to be dead, and self-injurious 
behavior without suicidal intent.  
In addition, the number and percent of patients who experienced at least one of various 
composite measures will be presented and compared.  These include suicidal behavior 
(completed suicide, non-fatal suicidal attempts, interrupted attempts, aborted attempts, and 
preparatory acts or behavior), suicidal ideation (active suicidal ideation with specific plan and 
intent, active suicidal ideation with some intent to act without specific plan, active suicidal 
ideation with any methods [no plan] without intent to act, non-specific active suicidal thoughts, 
and wish to be dead), and suicidal ideation or behavior.  
Specifically, the following outcomes are C-SSRS categories and have binary responses (yes/no).  
The categories have been re-ordered from the actual scale to facilitate the definitions of the 
composite and comparative endpoints, and to enable clarity in the presentation of the results.  
Category 1 – Wish to be Dead
Category 2 – Non-specific Active Suicidal Thoughts


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 14
LY2951742
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Category 5 – Active Suicidal Ideation with Specific Plan and Intent
Category 6 – Preparatory Acts or Behavior 
Category 7 – Aborted Attempt
Category 8 – Interrupted Attempt
Category 9 – Actual Attempt (non-fatal)
Category 10 – Completed Suicide
Self-injurious behavior without suicidal intent is also a C-SSRS outcome (although not suicide-
related) and has a binary response (yes/no).  
Composite endpoints based on the above categories are defined below.

Suicidal ideation:  A “yes” answer at any time during treatment to any 1 of the 
5 suicidal ideation questions (Categories 1-5) on the C-SSRS.

Suicidal behavior:  A “yes” answer at any time during treatment to any 1 of 
the 5 suicidal behavior questions (Categories 6-10) on the C-SSRS.

Suicidal ideation or behavior:  A “yes” answer at any time during treatment to 
any 1 of the 10 suicidal ideation and behavior questions (Categories 1-10) on 
the C-SSRS. 
Patients who discontinued from the study with no postbaseline C-SSRS value will be considered 
unevaluable for analyses of suicide-related events.  Only evaluable patients will be considered in 
the analyses.
5.16.6. Vital Signs and Weight
Vital signs collected during the study include systolic and diastolic blood pressure (BP), pulse, 
and temperature. BP and pulse measurements will be taken when the patient is in a sitting 
position. Three measurements of sitting BP and pulse will be collected at approximately 30 to 
60 second intervals at every office visit and the 3 sitting BP measurements and 3 pulse values
will be averaged and used as the value for that visit. 
Table CGAR.5.1 displays the criteria used to define categorical changes of interest in vital signs
and weight.  The last column of the table displays the patient population for each analysis based 
on baseline categories.  The number and percent of patients meeting these criteria will be 
summarized.
The criteria to identify patients with treatment-emergent abnormal changes generally consist of 
2 parts, an absolute threshold and a change from baseline amount. 

The absolute threshold in the criteria is based on 1) minimum postbaseline when 
the direction is low; 2) maximum postbaseline when the direction is high.


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 15
LY2951742

The change from baseline amount in the criteria is 1) decrease from baseline to 
minimum postbaseline when the direction is low; 2) increase from baseline to 
maximum postbaseline when the direction is high.
The baseline for systolic BP, diastolic BP, and pulse is defined as the last non-missing baseline 
value during the baseline period. 
For categorical changes of interest in temperature and weight, the baseline values are defined 
below:

For the analyses of categorical changes of interest in temperature and weight,
o
the baseline is defined as the minimum value during baseline period when the 
direction is low
o
the baseline is defined as the maximum value during the baseline period when 
the direction is high
Table CGAR.5.1.
Categorical Changes of Interest in Vital Signs and Weight
Parameter
Direction
Criteria
Patients Population 
defined by Baseline 
Categories
Systolic BP (mm Hg) 
(sitting)
Low
≤90 and decrease ≥20
>90; 90; All patients
High
≥140 and increase ≥20
<140; 140; All patients
PCS High
≥180 and increase ≥20
<180; 180; All patients
Sustained Elevation
≥140 and increase ≥20 at 2 
consecutive visits
<140; 140; All patients
Diastolic BP (mm Hg)
(sitting)
Low
≤50 and decrease ≥10
>50; 50; All patients
High
≥90 and increase ≥10
<90; 90; All patients
PCS High
≥105 and increase ≥15
<105; 105; All patients
Sustained Elevation
≥90 and increase ≥10 at 2 
consecutive visits
<90; 90; All patients
Systolic BP or Diastolic 
BP (mm Hg)
(sitting)
Sustained Elevation
Meeting criteria for systolic BP 
for 2 consecutive visits or 
meeting criteria for diastolic BP 
for 2 consecutive visits or both
All patients
Pulse (bpm) (sitting)
Low
<50 and decrease ≥15
50; <50; All patients
High
>100 and increase ≥15
100; >100; All patients
Sustained Elevation
>100 and increase ≥15 at 2 
consecutive visits
≤100; >100; All patients
Weight (kg)
Low
(Loss) decrease ≥7%
All patients
High
(Gain) increase ≥7%
All patients
Temperature (F)
Low
<96F and decrease ≥2F
96F
High
≥101F and increase ≥2F
<101F


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 16
LY2951742
Abbreviations:  BP = blood pressure; PCS = Potentially Clinically Significant; mm Hg = millimeters of mercury; 
bpm = beats per minute; kg = kilograms; F = degrees Fahrenheit.  
5.16.7. Electrocardiogram Intervals and Heart Rate
Analyses of QTc interval, Fridericia’s corrected QT interval (QTcF) (msec), will be calculated 
with Fridericia’s formula as QT/RR⅓. For the QTc calculations, the unit for QT is milliseconds 
and the unit for RR is seconds.  For patients with QRS ≥120 milliseconds at any time during the 
study, the QT and QTc interval will be excluded from the analyses.  
The baseline for ECG is defined as the last non-missing baseline value during the baseline 
period.  This baseline definition for ECG applies to all analyses (quantitative and qualitative).
The number and percent of patients meeting criteria for treatment-emergent abnormalities in 
ECG intervals (PR, QRS, and QTcF) and heart rate will be summarized.
Table CGAR.5.2 displays the criteria for treatment-emergent changes in ECG intervals and heart 
rate.  

For treatment-emergent low analyses:  patients with normal or high values at baseline (no 
low values) will be included. 

For treatment-emergent high analyses:  patients with normal or low values at baseline (no 
high values) will be included. 

For treatment-emergent increase analyses:  patients with a baseline and at least one 
postbaseline result will be included. 
Table CGAR.5.2.
Criteria for Treatment-Emergent Changes in ECG Intervals and 
Heart Rate
Parameter
Direction
Criteria
Heart Rate (bpm)
Low
<50 and decrease ≥15
High
>100 and increase ≥15
PR Interval (msec)
Low
<120
High
≥220
QRS Interval (msec)
Low
<60
High
≥120
QTcF (msec)
Low
Males:  <330
Females:  <340
High
Males:  >450
Females:  >470
PCS High
>500msec
Increase
Increase >30 msec
Increase >60 msec
Increase >75 msec


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 17
LY2951742
Abbreviations:  bpm = beats per minute; ECG = electrocardiogram; PCS = Potentially Clinically Significant; QTcF 
= Fridericia’s corrected QT interval.
In addition, qualitative ECG abnormalities will be evaluated which will include 11 ECG 
categories (axis, rhythm, conduction, ischemia, infarction, injury, morphology, U-waves, T-
waves, ST Segment, and other abnormalities) of qualitative findings. A category is a collection 
of possible descriptions (findings) of one qualitative aspect of an ECG.  A category name is the 
name of the qualitative aspect of the ECG (for example, rhythm, conduction, morphology, 
ischemia, and so forth). A finding is one of the possible specific descriptions (for example, sinus 
bradycardia, acute septal infarction) within a category. 
A shift table summary of qualitative ECGs at any time will be produced, to assess shifts from 
baseline normal to postbaseline abnormal for the overall ECG and for each of the 11 finding 
categories mentioned above.
Patients with the following are excluded from ECG analyses: lead reversals or <9 leads, 
nonmatching demographic data, and those suggesting patient identification errors.
5.16.8. Laboratory Tests
The number and percent of patients with treatment-emergent abnormal, high, or low laboratory 
values for each laboratory test based on Covance reference ranges will be summarized.  
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.
5.16.9. Immunogenicity
In the immunogenicity assay process, each sample is potentially examined multiple times, 
according to a hierarchical procedure, to produce a sample ADA assay result and potentially a 
sample NAb assay result.  The cut points used, the drug tolerance of an assay, and the possible 
values of titers are operating characteristics of the assay.
It can be the case that the presence of high concentrations of galcanezumab will affect the 
measurements of the presence of ADA or NAb, and conversely high levels of ADA or NAb may 
affect the measurement of GMB concentration.  Thus an GMB drug concentration, assessed from 


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 18
LY2951742
a sample drawn at the same time as the ADA sample, plays a key role in clinical interpretation of 
a sample when the laboratory result is Not Detected.
5.16.9.1. Definitions of Patient ADA Status
Patient evaluable for TE ADA:  A patient is evaluable for TE ADA if the patient has a 
non-missing baseline ADA result, and at least 1 non-missing postbaseline.
TE ADA positive (TE ADA+) patient:  A patient who is evaluable for TE ADA is TE ADA+ if 
either of the following holds:

Treatment-induced: The patient has baseline status of ADA Not Present and at least 
one postbaseline status of ADA Present with titer ≥20 (that is, 2* MRD where for
this ADA assay the MRD, the minimum required dilution of the ADA assay, is 10).  

Treatment-boosted:  The patient has baseline and postbaseline status of ADA 
Present, with the postbaseline titer being 2 dilutions (4-fold) greater than the baseline 
titer. That is, the patient has baseline status of ADA Present, with titer 1:B, and at 
least one postbaseline status of ADA Present, with titer 1:P, with P/B ≥4.  
5.16.9.2. Immunogenicity Analyses to be Performed
To evaluate changes in immunogenicity data (ADA and NAb) after treatment, the number and
percent of TE ADA evaluable patients who are TE ADA+ in Study CGAR will be tabulated.
The following analyses are planned:

The incidence of TE ADA+ patients in CGAR postbaseline, by previous TE ADA status 
in the parent study (CGAL or CGAM) and at CGAR baseline.  Because patients who 
enter Study CGAR will have differing levels of previous GMB exposure (0 to 15 
months), this immunogenicity analysis will categorize patients in 3 groups, according to 
their previous GMB exposure in the parent study:
o
Study CGAL patients who received placebo (0 months of GMB treatment)
o
Study CGAL patients who received GMB (2 months of GMB treatment)
o
Study CGAM patients (12 or 15 months of GMB treatment)

A listing of patients with TE ADA in CGAR postbaseline, including ADA and NAb 
results from both the parent study and CGAR.
Reports to Be Generated at Each Interim and Final Database 
Lock
5.17.1. Report to Be Generated at Interim Database Locks
Two interim locks will occur prior to the final database lock for CGAR, to support the regulatory 
submission and safety update report, respectively.  The first lock will occur after all patients in 
both parent studies (CGAL and CGAM) have had the chance to complete the double-blind 
treatment phase, and the corresponding Synopsis CSR will include any data up to the cutoff date 
of 27 March 2018.  The second lock for a safety update report will include any data up to the 


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 19
LY2951742
cutoff date of 04 September 2018.  The analyses for these two interim locks will focus on the 
following topics:

patient disposition

patient characteristics

exposure to investigational products

AE overview, TEAE, SAE, and DCAE
5.17.2. Report to Be Generated at Final Database Lock
For final database lock, all analyses defined in this SAP, including tables, figures, and listings,
will be generated.
Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  These analyses will be the responsibility of the Sponsor.  
Analyses provided for the CTR requirements include the following:
A summary of AEs will be provided as a dataset that will be converted to an XML file.  Both 
Serious Adverse Events and ‘Other’ Adverse Events are summarized: by MedDRA PT.

An AE is considered “Serious” whether or not it is a TEAE.

An AE is considered in the “Other” category if it is both a TEAE and is not serious.  For 
each “Serious” AE and “Other” AE, for each term, the following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced

Consistent with www.ClinicalTrials.gov requirements, “Other” AEs that occur in fewer 
than 5% of patients in the treatment group may not be included if a 5% threshold is 
chosen.

AE reporting is consistent with other document disclosures, for example, the CSR, 
manuscripts, and so forth.


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 20
LY2951742
6.
Reference
Brooks R. EuroQol: the current state of play. Health Policy. 1996;37(1):53-72.
[EuroQol] EuroQol Group. EuroQol—a new facility for the measurement of health-related 
quality of life. Health Policy. 1990;16(3):199-208.
Guy W. ECDEU assessment manual for psychopharmacology, revised 1976. Rockville, MD: 
National Institute of Mental Health, Psychopharmacology Research Branch. p 217-222. 
Available at: https://archive.org/details/ecdeuassessmentm1933guyw. Accessed September 29, 
2014.
Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, Bonsel G, Badia X. Development 
and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 
2011;20(10):1727-1736.
Stafford MR, Hareendran A, Ng-Mak DS, Insinga RP, Xu R, Stull DE. EQ-5D™-derived utility 
values for different levels of migraine severity from a UK sample of migraineurs. Health Qual 
Life Outcomes. 2012;10:65.
Van Reenen M, Janssen B. EQ-5D-5L User Guide: Basic information on how to use the EQ-5D-
5L instrument, version 2.1. 2015. Available at: 
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
5L_UserGuide_2015.pdf. Accessed January 18, 2016.


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 21
LY2951742
7.
Appendices


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 22
LY2951742
Appendix 1.
Important Protocol Deviations
Category
(sCTMS)
Sub Category 
(sCTMS)
Trial-specific Term
Source
Informed 
Consent
Informed 
consent not 
obtained
NA
Programmable/Non-
programmable–Monitor 
identified
Informed 
Consent
Revoke 
Consent
NA
Non-programmable–
Monitor identified
Eligibility
Inclusion/
Exclusion
Exclusionary
cardiovascular-related condition
Programmable/Non-
programmable–Monitor 
identified
Eligibility
Inclusion/
Exclusion
Exclusionary
hepatobiliary elevation
Programmable/Non-
programmable–Monitor 
identified
Eligibility
Inclusion/
Exclusion
Positive exclusionary UDS for
any substances of abuse
Programmable/Non-
programmable–Monitor 
identified
Eligibility
Inclusion/
Exclusion
Inadvertent enrollment
Non-programmable–
Monitor identified
Study 
Procedures
Excluded Con 
Meds
Use of verapamil at doses higher 
than allowed at baseline and 
during study
Programmable/Non-
programmable–Monitor 
identified
Study 
Procedures
Other
C-SSRS not completed at required 
visits
Programmable/Non-
programmable–Monitor 
identified
Study 
Procedures
Other
Missing all 3 BP, or all 3 Pulse 
Programmable/Non-
programmable–Monitor 
identified
Study 
Procedures
Other
Missing scheduled ECG
Programmable/Non-
programmable–Monitor 
identified
Study 
Procedures
Other
Discontinuing without the 1 
month post injection office visit 
(Event List F)
Programmable/Non-
programmable–Monitor 
identified


I5Q-MC-CGAR Statistical Analysis Plan Version 3
Page 23
LY2951742
Category
(sCTMS)
Sub Category 
(sCTMS)
Trial-specific Term
Source
Safety
SAEs
Site did not appropriately report 
SAEs
Nonprogrammable –
Monitor identified
Safety
Other
Female patients who are dosed 
who have a positive urine and/or 
serum pregnancy test
Programmable
Investigational 
Product
Patient took 
medication not 
fit for use
Patient received drug that was 
declared “Not Fit for Use”
Nonprogrammable –
Monitor identified
Investigational 
Product
Other
Administering galcanezumab less 
than 21 days between doses
Programmable
Investigational 
Product
Dosing Error
Other Significant violations of 
study drug dosing
Nonprogrammable –
Monitor identified
Investigational 
Product
Other
IP lost or stolen
Nonprogrammable –
Monitor identified
Administrative/
Oversight
Suspected 
Misconduct
NA
Nonprogrammable –
Monitor identified
Administrative/
Oversight
Suspected 
Misconduct
Suspected Fraud
Nonprogrammable –
Monitor identified
Administrative/
Oversight
Suspected 
Misconduct
Suspected falsification of data
Nonprogrammable –
Monitor identified
Administrative/
Oversight
Other
C-SSRS scale administered by 
unqualified rater
Nonprogrammable –
Monitor identified
Administrative/
Oversight
Other
Quality issue at site or vendor
Nonprogrammable –
Monitor identified
Administrative 
Oversight
Other
Privacy Breach
Nonprogrammable –
Monitor identified
Abbreviations: BP = blood pressure; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram;
IP = investigational product; NA = Not Applicable; SAE = serious adverse event.


Leo Document ID = 45d3c3c2-da39-4860-9fa7-c1819cbcfb26
Approver: 
Approval Date & Time: 02-Mar-2021 18:12:37 GMT
Signature meaning: Approved
PPD