Clinical trial NCT02397473
Conditions: Episodic Cluster Headache
Sponsor: Eli Lilly and Company
Start date: 2015-05-22; Completion date: 2018-06-04
Enrollment: 109 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the efficacy and safety of the study drug known as Galcanezumab in participants with episodic cluster headaches.

Detailed description:

Arms: arm 1: Galcanezumab 300mg administered subcutaneously (SC) every 30 days during an 8 week treatment period. arm 2: Placebo administered SC every 30 days during an 8 week treatment period.
Interventions: intervention 1: Galcanezumab intervention 2: Placebo
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_001.pdf: 
Protocol I5Q-MC-CGAL(d)  
 
 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of LY2951742 in Patients with 
Episodic Cluster Headache  
 
 
NCT02397473 
 
 
Approval Date: 29-Mar-2018 
 
 


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1. Protocol I5Q-MC-CGAL(d)
A Phase 3 Randomized, Double-Blind, Placebo-Controlled
Study of LY2951742 in Patients with Episodic Cluster 
Headache
Confidential Information
The information contained in this protocol 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, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  This document and its associated attachments are 
subject to United States Freedom of Information Act (FOIA) Exemption 4.
LY2951742
Study CGAL is a Phase 3 multi-center, outpatient, randomized, double-blind, placebo-
controlled study of LY2951742 300 mg in the prevention of episodic cluster headache.  The 
study consists of 4 study phases (SP):  SP I (screening/washout), SP II (pre-randomization 
diary), SP III (randomized, double-blind, placebo-controlled treatment), and SP IV (post-
treatment follow-up).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 18 December 2014
Amendment (a) Electronically Signed and Approved by Lilly:  12 February 2015
Amendment (b) Electronically Signed and Approved by Lilly:  22 December 2015      
Amendment (c) Electronically Signed and Approved by Lilly:  10 February 2017
Amendment (d) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 29-Mar-2018 GMT


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2.
Synopsis
Study Rationale
LY2951742 (also known as galcanezumab) is a humanized monoclonal antibody that selectively binds to and 
neutralizes calcitonin-gene-related-peptide (CGRP) and 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 LY2951742 to date 
for the prevention of migraine support the evaluation of the CGRP neutralizing antibody LY2951742 for the 
treatment of cluster headache.
The aim of this study is to assess the safety and efficacy of LY2951742 300 mg every 30 days in the prevention of 
episodic cluster headache.
Clinical Protocol Synopsis:  Study I5Q-MC-CGAL
Name of Investigational Product: LY2951742 (a humanized monoclonal antibody that binds to and neutralizes 
CGRP)
Title of Study:  A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of LY2951742 in Patients with
Episodic Cluster Headache
Number of Planned Patients:
   Entered:  231
   Enrolled/Randomized: Planned 162
   Completed:  146
Phase of Development:  3
Length of Study:  approximately 18 months
Estimated first patient visit:  Apr 2015               Estimated last patient visit:  Sep 2016
Primary Objective:  The primary objective of this study is to assess the efficacy of LY2951742 300 mg every 
30 days compared with placebo in reducing the frequency of weekly cluster headache attacks in patients with 
episodic cluster headache.  The primary outcome measure will be the weekly cluster headache attack frequency. The 
primary endpoint will be the overall mean change from baseline in weekly cluster headache attack frequency across 
Weeks 1 to 3 with LY2951742 compared with placebo.  Baseline is defined as the last 7 days in the eligibility report 
(pre-randomization diary phase).
Gated Objective: To assess the efficacy of LY2951742 compared with placebo in the proportion of patients meeting 
response at Week 3.  For this analysis, response is defined as a reduction from baseline of 50% or greater in the 
weekly cluster headache attack frequency.


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Other Secondary Objectives:

To assess whether LY2951742 is superior to placebo on the following:
a.
The proportion of patients with a 50% or greater reduction in the weekly number of cluster headache 
attacks from baseline for each weekly interval through Week 8
b.
The proportion of patients with a 30% or greater reduction in the weekly number of cluster headache 
attacks from baseline for each weekly interval through Week 8
c.
Mean change in the weekly cluster headache attack frequency from baseline for each weekly interval
through Week 8
d.
Proportion of patients reporting a score of 1 (“very much better”) or 2 (“much better”) on the Patient 
Global Impression of Improvement (PGI-I) at Week 4 and Week 8.

To compare the safety and tolerability of LY2951742 with placebo in patients with episodic cluster 
headache using the following measures:
a.
spontaneously reported treatment-emergent adverse events (TEAEs)
b.
serious adverse events (SAEs)
c.
discontinuation rates
d.
suicidal ideation and behaviors assessed by solicited questioning using the Columbia-Suicide Severity 
Rating Scale (C-SSRS).

To assess the development and consequences of anti-drug antibodies (ADA) to LY2951742 in patients 
exposed to LY2951742; to provide samples for subsequent evaluation of neutralizing ADA (NAb).

To evaluate the pharmacokinetics (PK) of LY2951742.
Exploratory Objectives: To assess whether LY2951742 is superior to placebo as measured by:

Mean change in the weekly number of times an abortive medication was taken from baseline for each 
weekly interval through Week 8 comparing LY2951742 with placebo.

Change in percentage of times using oxygen from baseline for each weekly interval through Week 8 
comparing LY2951742 with placebo.

Change in percentage of times using triptan from baseline for each weekly interval through Week 8 
comparing LY2951742 with placebo.

Change in percentage of times of using acetaminophen/paracetamol or NSAIDs from baseline for each 
weekly interval through Week 8 comparing LY2951742 with placebo.

The proportion of patients with a 75% or greater reduction in the weekly number of cluster headache attacks 
from baseline for each weekly interval through Week 8 comparing LY2951742 with placebo.

The proportion of patients with a 100% reduction in the weekly number of cluster headache attacks from 
baseline for each weekly interval through Week 8 comparing LY2951742 with placebo.

Mean change in the cluster headache attack average weekly pain severity (based on 5-point scale) from 
baseline through Week 8 comparing LY2951742 with placebo.
Study Design:  Phase 3 multi-center, outpatient, randomized, double-blind, placebo-controlled study of LY2951742 
300 mg once monthly compared with placebo for the prevention of episodic cluster headache.  The study has 4 study 
phases (SP): SP I (screening/washout), SP II (pre-randomization diary), SP III (randomized, double-blind, placebo-
controlled treatment), and SP IV (post-treatment follow-up).
Diagnosis and Main Criteria for Inclusion and Exclusions:  The planned patient population are adult outpatients 
(18 to 65 years of age inclusive) who meet the International Classification of Headache Disorders, Third Edition, 
beta version, or ICHD-3-beta, diagnostic criteria for Episodic Cluster Headache and have a baseline weekly cluster 
headache attack frequency of 1) a maximum of 8 attacks per day and 2) a minimum of 1 cluster headache attack 
every other day and at least 4 total attacks during baseline assessment.  Patients must also have a prior history of a 
cluster period lasting at least 6 weeks and should be able to distinguish cluster headache attacks from other headaches 
(i.e. tension-type headaches, migraine).  Patients are excluded from study participation if they are currently enrolled 
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in another clinical trial, are using or have used CGRP or nerve growth factor (NGF) antibodies, have a lifetime 
history of migraine variants that could implicate or could be confused with ischemia, are taking indomethacin and/or 
are suspected of having another distinct trigeminal autonomic cephalalgia, or have had botulinum toxin type A or B 
administered in the head or neck area within 4 months of SP II.
Investigational Product, Dosage, and Mode of Administration or Intervention:  LY2951742 300 mg 
administered every 30 days as three 1-mL subcutaneous (SC) injections 
Reference Therapy, Dose, and Mode of Administration or Comparative Intervention:  placebo (0.9% Sodium 
Chloride Injection, USP; volume matched) administered every 30 days as three 1-mL SC injections
Planned Duration of Treatment: 8 weeks double-blind treatment + up to 16 weeks post-treatment follow-up
Screening/washout phase:  minimum of 0 days to maximum of 12 months 
Pre-randomization diary phase:  10 to 15 days
Treatment phase:  8 weeks
Post-treatment follow-up phase:  16 weeks
Criteria for Evaluation:
Efficacy:
Electronic Patient Reported Outcome (ePRO) Diary:  Patients will be asked to record the number of cluster 
headache attacks in their daily ePRO diary during SP II and SP III.  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.
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.
Safety:
Safety will be assessed by summarizing and analyzing adverse events (AEs), laboratory test results, vital signs, 
electrocardiograms (ECGs) and suicidal ideation/behavior (via the C-SSRS).
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Statistical Methods:
Statistical:  The study is planned to have a minimum of approximately 162 patients randomized 1:1 to placebo or 
LY2951742 with the opportunity to increase the final sample size at an interim analysis if indicated in order to 
maintain a well powered study.  To preserve blinding, details of the sample size and power calculations are omitted 
from this protocol and are provided in a separate document to the Ethical Review Board (ERB).
Unless otherwise specified, efficacy analyses during SP III will be conducted on an intent-to-treat (ITT) population, 
which include all patients who are randomized and receive at least 1 dose of investigational product (IP).  Patients in 
the ITT population will be analyzed according to the treatment group to which they were randomized.  Safety 
analyses during SP III will be conducted on the safety population, which also includes all patients who were 
randomized and receive at least 1 dose of study drug.  However, patients will be analyzed by actual study treatment 
received most often (modal treatment) during the double-blind treatment phase .  When change from baseline is 
assessed, the patient will be included in the analysis only if he/she has a baseline and a post-baseline measurement.  
For analyses of the post-treatment phase, the post-treatment population will be used.  Post-treatment population will 
be defined as all patients who entered the post-treatment phase (SP IV) as indicated by entering any post-treatment 
visit.  Details related to handling of missing data will be described in the statistical analysis plan (SAP).
Treatment effects will be evaluated based on a 2-sided significance level of 0.05 for all the efficacy and safety 
analyses unless otherwise stated.  The 95% confidence intervals (CIs) for the difference between treatment groups 
will be presented.  Adjustments for multiple comparisons for the analyses corresponding to the primary and gated 
secondary objectives are described in the sections on the primary and secondary efficacy analyses below.  There will 
be no adjustments for multiplicity for analyses of other data.
    
Categorical comparisons between treatment groups will be performed using Fisher’s exact tests, where appropriate.
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 changes, will be described in the SAP and/or in the clinical study report.
Additional exploratory analyses of the data will be conducted as deemed appropriate.
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its designee.  SAS® software 
will be used to perform most or all statistical analyses.
Efficacy – Primary: The primary analysis will be conducted by a restricted maximum likelihood-based (REML-
based), mixed-effects repeated measures (MMRM) analysis using all the longitudinal observations from Week 1 to 
Week 3.  The analysis of the primary outcome will be the main effect of treatment between LY2951742 300 mg and 
placebo across Weeks 1 to 3 of the treatment phase from a repeated measures analysis on mean change from baseline 
in the weekly attack frequency.  This provides the average treatment effect over the 3-week period.  Baseline is 
defined as the last 7 days in the eligibility report (pre-randomization diary phase).
Efficacy – Gated Secondary: The gated secondary outcome, 50% response, is the proportion of patients meeting the 
response criteria at Week 3 and will be assessed using Fisher’s exact test.  A non-responder imputation for missing 
values will be used.  Specifically, all patients who discontinue study treatment at any time prior to Week 3, for any 
reason, will be considered a non-responder at all missing assessments.


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Safety:  The safety analyses will be conducted for SP III and SP IV.
The safety and tolerability of treatment will be assessed by summarizing the following:

AEs
o
TEAEs 

By preferred term

By system organ class

By maximum severity 

Considered to be related to IP by investigator
o
Serious Adverse Events (SAEs)
o
AE leading to discontinuation

Suicidal ideation and behaviors assessed by solicited questioning using the C-SSRS

Vital signs and weight

ECGs

Laboratory measurements

Anti-drug antibody
Unless specified otherwise, the categorical safety analyses will include both schedule and unscheduled visits.  
Comparisons between treatment groups for all categorical safety measures will be made using Fisher’s exact test for 
SP III with the safety population.  Descriptive statistics only will be presented for the treatment groups in SP IV with 
the post-treatment population.
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3. Table of Contents
A Phase 3 Randomized, Double-Blind, Placebo-Controlled 
Study of LY2951742 in Patients with Episodic Cluster 
Headache
Section
Page
1.
Protocol I5Q-MC-CGAL(d) A Phase 3 Randomized, Double-Blind, 
Placebo-Controlled Study of LY2951742 in Patients with Episodic 
Cluster Headache ................................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................7
4.
Abbreviations and Definitions...........................................................................................12
5.
Introduction ......................................................................................................................17
6.
Objectives.........................................................................................................................20
6.1.
Primary Objective ........................................................................................................20
6.2.
Secondary Objectives...................................................................................................20
6.2.1.
Gated Objective ...................................................................................................20
6.2.2.
Other Secondary Objectives .................................................................................20
6.3.
Exploratory Objectives.................................................................................................21
7.
Investigational Plan...........................................................................................................22
7.1.
Summary of Study Design............................................................................................22
7.2.
Discussion of Design and Control ................................................................................24
8.
Study Population...............................................................................................................25
8.1.
Inclusion Criteria..........................................................................................................25
8.1.1.
Disease Diagnostic Criteria ..................................................................................27
8.2.
Exclusion Criteria ........................................................................................................27
8.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................30
8.3.
Rescreening..................................................................................................................30
8.4.
Discontinuations ..........................................................................................................32
8.4.1.
Discontinuation of Inadvertently Enrolled Patients...............................................32
8.4.2.
Discontinuation of Investigational Product...........................................................32
8.4.3.
Patient Discontinuation from the Study ................................................................33
8.4.4.
Patients Lost to Follow-Up...................................................................................34
8.4.5.
Discontinuation of Study Sites .............................................................................34
8.4.6.
Discontinuation of the Study................................................................................34
9.
Treatment..........................................................................................................................35


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9.1.
Treatments Administered .............................................................................................35
9.2.
Materials and Supplies .................................................................................................35
9.3.
Method of Assignment to Treatment ............................................................................36
9.4.
Rationale for Selection of Doses in the Study...............................................................36
9.5.
Selection and Timing of Doses.....................................................................................36
9.6.
Continued Access to Investigational Product................................................................37
9.7.
Blinding .......................................................................................................................37
9.8.
Concomitant Therapy...................................................................................................37
10.
Efficacy, Safety Evaluations, Sample Collection and Testing, and 
Appropriateness of Measurements.....................................................................................39
10.1. Efficacy Measures........................................................................................................39
10.1.1.
Primary Efficacy Measure....................................................................................39
10.1.2.
Secondary Efficacy Measure................................................................................39
10.2. Safety Evaluations........................................................................................................39
10.2.1.
Adverse Events ....................................................................................................39
10.2.1.1.
Serious Adverse Events ..................................................................................40
10.2.1.1.1.
Suspected Unexpected Serious Adverse Reactions....................................41
10.2.2.
Other Safety Measures .........................................................................................41
10.2.2.1.
Electrocardiograms.........................................................................................41
10.2.2.2.
Vital Signs......................................................................................................42
10.2.2.3.
Columbia-Suicide Severity Rating Scale, Self-Harm 
Supplement Form, and Self-Harm Follow-up Form ........................................43
10.2.3.
Safety Monitoring ................................................................................................43
10.2.4.
Complaint Handling.............................................................................................43
10.3. Sample Collection and Testing.....................................................................................44
10.3.1.
Samples for Study Qualification and Health Monitoring.......................................44
10.3.2.
Samples for Biomarker Research..........................................................................44
10.3.4.
Samples for Non-genetic Biomarker Research......................................................45
10.3.5.
Samples for Immunogenicity Research.................................................................46
10.4. Appropriateness of Measurements................................................................................46
11.
Data Quality Assurance.....................................................................................................47
11.1. Data Capture System....................................................................................................47
12.
Sample Size and Statistical Methods .................................................................................49
12.1. Determination of Sample Size ......................................................................................49
12.2. Statistical and Analytical Plans.....................................................................................49
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12.2.1.
General Considerations ........................................................................................49
12.2.2.
Patient Disposition...............................................................................................50
12.2.3.
Patient Characteristics..........................................................................................50
12.2.4.
Concomitant Therapy...........................................................................................50
12.2.5.
Treatment Compliance .........................................................................................50
12.2.6.
ePRO Diary Compliance......................................................................................51
12.2.7.
Primary and Gated Outcome and Methodology....................................................51
12.2.7.1.
Primary Outcome ...........................................................................................51
12.2.7.2.
Gated Secondary.............................................................................................52
12.2.8.
Other Efficacy Analyses.......................................................................................52
12.2.10. Safety Analyses....................................................................................................53
12.2.10.1. Categorical Safety Variables...........................................................................53
12.2.10.2. Adverse Events...............................................................................................53
12.2.10.3. Suicide-Related Thoughts and Behaviors........................................................53
12.2.10.4. Vital Signs and Weight...................................................................................54
12.2.10.5. Electrocardiogram Intervals and Heart Rate....................................................54
12.2.10.6. Laboratory Tests.............................................................................................54
12.2.10.7. Immunogenicity Analyses ..............................................................................55
12.2.11. Subgroup Analyses ..............................................................................................55
12.2.12. Interim Analyses..................................................................................................55
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................56
13.1. Informed Consent.........................................................................................................56
13.2. Ethical Review.............................................................................................................56
13.3. Regulatory Considerations ...........................................................................................56
13.3.1.
Investigator Information.......................................................................................57
13.3.2.
Protocol Signatures ..............................................................................................57
13.3.3.
Final Report Signature .........................................................................................57
14.
References ........................................................................................................................58
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List of Figures
Figure
Page
Figure CGAL.1. Illustration of study design for clinical protocol I5Q-MC-CGAL. ..................22


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List of Attachments
Attachment
Page
Attachment 1.
Protocol CGAL Study Schedule.....................................................................60
Attachment 2.
Protocol CGAL Clinical Laboratory Tests .....................................................68
Attachment 3.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................70
Attachment 4.
Protocol CGAL Sampling Summary..............................................................71
Attachment 5.
Protocol Amendment Summary:  I5Q-MC-CGAL(d).....................................72


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4. Abbreviations and Definitions
Term
Definition
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ADA
anti-drug antibodies
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANOVA
analysis of variance
ACOVA
analysis with analysis of covariance
AST
aspartate aminotransferase
audit
A systematic and independent examination of the trial-related activities and documents 
to determine whether the evaluated trial-related activities were conducted, and the data 
were recorded, analyzed, and accurately reported according to the protocol, applicable 
standard operating procedures (SOPs), good clinical practice (GCP), and the applicable 
regulatory requirement(s).
blinding
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
BMI
body mass index
BUN
blood urea nitrogen
CGRP
calcitonin-gene-related peptide
CIDBF
capsaicin-induced dermal blood flow
CIOMS
Council for International Organizations of Medical Sciences
CMH
Cochran-Mantel-Haenszel
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.


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compliance
Adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements 
defined by the laboratory generating the data and that Eli Lilly and Company (Lilly) is 
confident that results are accurate.  Confirmation will either occur immediately after 
initial testing or will require that samples be held to be retested at some defined time 
point, depending on the steps required to obtain confirmed results.
CRP/CRS
clinical research physician (CRP): Individual responsible for the medical conduct of 
the study.  Responsibilities of the CRP may be performed by a physician, clinical 
research scientist (CRS), global safety physician or other medical officer.
C-SSRS
Columbia-Suicide Severity Rating Scale
DMC
data monitoring committee
ECG
electrocardiogram
efficacy
Efficacy is the ability of a treatment to achieve a beneficial intended result under 
controlled conditions.
end of trial (study)
End of trial is the date of the last visit or last scheduled procedure shown in the Study 
Schedule for the last patient.
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 informed consent form directly or 
through their legally acceptable representatives.
ePRO
electronic patient reported outcome
ERB/IRB
ethical review board/institutional review board:  A board or committee (institutional, 
regional, or national) composed of medical and nonmedical members whose 
responsibility is to verify that the safety, welfare, and human rights of the patients 
participating in a clinical study are protected.
FSH
follicle stimulating hormone
GCP
good clinical practice
GPS
Global Patient Safety
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
ICHD-3
International Classification of Headache Disorders-3 beta
IHS
International Headache Society
IND
Investigational New Drug application


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INR
international normalized ratio
informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular trial, after having been informed of all aspects of the trial that are relevant 
to the patient’s decision to participate.  Informed consent is documented by means of a 
written, signed, and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product (IP)
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a study is 
conducted by a team of individuals at a study site, the investigator is the responsible 
leader of the team and may be called the principal investigator.
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IWRS
interactive web-response system
legal representative
An individual, judicial, or other body authorized under applicable law to consent on 
behalf of a prospective patient, to the patient’s participation in the clinical study.
LLT
lowest level term
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
MMRM
mixed model repeated measures
msec
milliseconds
NAb
neutralizing anti-drug antibodies
NGF
nerve growth factor
OTC
over the counter
patient
A study participant who has the disease or condition for which the investigational 
product is targeted.
PD
pharmacodynamics
PGI-I
Patient Global Impression of Improvement


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PK
pharmacokinetics
PR
pulse rate
PT
preferred term
QTc
corrected QT interval
QTcF
corrected QT interval measured with Fridericia’s formula
QTcLCTPB
Large Clinical Trial Population Based QT Correction
Randomize
The process of assigning patients to an experimental group on a random basis.  For this 
study, the terms enrolled and randomized are interchangeable.
RBC
red blood cells
REML
restricted maximum likelihood-based
rescreen
To screen a patient who was previously declared a screen failure for the same study.
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.  In this study, 
screening involves diagnostic procedures and/or tests (for example, diagnostic 
psychological tests, x-rays, blood draws).  For this type of screening, informed consent 
for these screening procedures and/or tests shall be obtained; this consent may be 
separate from obtaining consent for the study.
SD
standard deviation
SHSF
Self-Harm Supplement Form
SHFU
Self-Harm Follow-Up Form
SOC
system organ class
subject
An individual who is or becomes a participant in clinical research, either as a recipient 
of the investigational product(s) or as a control.  A subject may be either a healthy 
human or a patient.
SUNCT (SUNA)
short-lasting unilateral neuralgiform headache attacks
SUSARs
suspected unexpected serious adverse reactions
TBL
total bilirubin


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TEAE
treatment-emergent adverse event:  Any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to 
have a causal relationship with this treatment.
TPO
third-party organization
UA
unstable angina
UDS
urine drug screen
ULN
upper limit of normal
WBC
white blood cells


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LY2951742
A Phase 3 Randomized, Double-Blind, Placebo-Controlled 
Study of LY2951742 in Patients with Episodic Cluster 
Headache
5. Introduction
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 by the ICHD-3.  The natural course of illness of 
cluster headache can be conceptualized as consisting of two phases:  (1) cluster periods
(typically lasting weeks or months) composed of a series of 15 to 180 minute attacks of severe 
(often excruciating) unilateral headache pain attacks and cranial autonomic symptoms occurring 
near-daily to multiple times daily during the cluster period, and (2) attack-free remission periods 
that may last for weeks, months, or even years.  In addition, the ICHD-3 provides an operational 
distinction between two subtypes of cluster headache, episodic cluster headache (the 
predominant form) and chronic cluster headache (affecting up to 20% of all cluster headache 
sufferers (Manzoni et al. 1983; van Vliet et al. 2003), based on the duration of the attack-free 
remission:  ≥1 month for episodic, <1 month for chronic (Matharu and Goadsby 2002; 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 10-cm scale; Torelli and Manzoni 2003). 
The verbatim descriptors of the pain experienced by patients are varied and complex, including
drill; point; needle; punch; spear; stab wound; knife wound; stinging; piercing; shooting; 
hammer; pangs; throbbing; pulsating; and rhythmic (Torelli and Manzoni 2003).  In the United 
States, there is only one approved abortive medication (treatment initiated at the start of the 
attack to shorten the overall duration of the attack); limited to only twice-daily use, and no 
approved preventive medications.  The desperation in this patient population is exemplified by 
approximately half of patients reporting self-injurious behavior during attacks (Rozen and 
Fishman 2012) and many patients turning to illicit drug use, such as marijuana, cannabinoids, 
and hallucinogens (psilocybin, LSD, and 2-Bromo LSD), in an attempt to alleviate their suffering 
(Karst et al. 2010; McGeeney 2012; Tepper and Stillman 2013).
Increased plasma or serum levels of calcitonin gene-related peptide (CGRP) have been 
associated with painful syndromes such as migraine and cluster headache (Edvinsson and 
Goadsby 1994).  Calcitonin gene-related peptide is a 37-amino acid neuropeptide member of a 
family of peptides that includes amylin, adrenomedullin and calcitonin, 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 
initially demonstrated in a study of patients with spontaneous cluster headache attacks who were 


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LY2951742
found to have elevated CGRP levels compared to controls (Edvinsson and Goadsby 1994).  The 
CGRP levels were normalized after successful treatment with either subcutaneous (SC) 
sumatriptan or oxygen inhalation.  In another study, CGRP blood levels were elevated in 18 
males during a nitroglycerin-induced cluster headache and returned to baseline after successful 
sumatriptan treatment or spontaneous recovery (Fanciullacci et al.1995; Fanciullacci et al. 1997).  
These data provide evidence that a treatment which neutralizes CGRP, such as a CGRP antibody, 
may be effective in managing cluster headache.
LY2951742 (also known as galcanezumab) is a humanized monoclonal antibody that binds to 
and neutralizes CGRP.  LY2951742 has been identified for clinical development in pain 
conditions relevant to the CGRP pathway such as migraine, and, in completed studies to date, 
LY2951742 was shown to alter plasma CGRP concentrations, which is consistent with the 
binding of the antibody (LY2951742) to CGRP.  The similarities between migraine and cluster 
headache, the role of CGRP in both disorders and the clinical efficacy observed with LY2951742 
to date for the preventive treatment of migraine support the evaluation of the CGRP neutralizing 
antibody LY2951742 for the treatment of cluster headache.
A single and multiple-dose ascending study (I5Q-MC-CGAA [CGAA]) in healthy subjects and a 
Phase 2a proof-of-concept study (I5Q-AR-ART-01[ART-01]) in migraine patients have been
completed (de Hoon et al. 2013; Dodick et al. 2014). In study CGAA, LY2951742 was 
administered subcutaneously to healthy subjects at single doses up to 600 mg, and as a multiple 
dose of 150 mg every other week for a total of four administrations. This study demonstrated 
that LY2951742 was well-tolerated and did not result in any serious adverse event (SAE)
(Investigator’s Brochure [IB], Section 6). There were no clinically meaningful differences 
between LY2951742 dose groups or between LY2951742 dose groups and placebo in the 
frequency of any adverse events (AEs) or changes from baseline in vital signs, clinical laboratory 
values, or electrocardiogram (ECG) parameters (de Hoon et al. 2013). Further details of the 
safety, pharmacokinetic (PK) and pharmacodynamics (PD) of LY2951742 may be found in the 
IB, Section 6.
In the proof-of-concept study, ART-01, LY2951742 was administered subcutaneously at 150 mg 
once every 14 days for six doses in patients with a history of episodic migraine. LY2951742 
significantly reduced the number of migraine headache days compared to placebo (p=0.003) at 
the 12-week endpoint (Dodick et al. 2014).  Treatment-emergent adverse events (TEAEs) 
reported at a rate of 5% or higher in LY2951742 and greater than placebo were upper respiratory 
tract infection, injection site pain, abdominal pain, dizziness, injection site erythema, rash, and 
hypertension (Dodick et al. 2014). LY2951742 did not cause any obvious changes in clinical 
chemistry or hematologic parameters and there was no apparent effect on heart rate, blood 
pressure or ECG measurements (QT-interval or QTcF-interval).
More information about the known and expected benefits, risks, and reasonably anticipated AEs 
of LY2951742 may be found in the IB. Information on AEs expected to be related to the 
investigational product (IP) 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 


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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.
This study, I5Q-MC-CGAL (CGAL), will assess the safety and efficacy of LY2951742 300 mg 
every 30 days in patients with episodic cluster headache.


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LY2951742
6. Objectives
6.1.
Primary Objective
The primary objective is to assess the efficacy of LY2951742 300 mg every 30 days compared 
with placebo in reducing the frequency of weekly cluster headache attacks in patients with 
episodic cluster headache. The primary outcome measure will be the weekly cluster headache 
attack frequency. The primary endpoint will be the overall mean change from baseline in weekly 
cluster headache attack frequency across Weeks 1 to 3 with LY2951742 compared with placebo.
Baseline is defined as the last 7 days in the eligibility report (pre-randomization diary phase).
6.2.
Secondary Objectives 
6.2.1. Gated Objective
To assess the efficacy of LY2951742 compared with placebo in the proportion of patients 
meeting response at Week 3. For this analysis, response is defined as a reduction from baseline 
of 50% or greater in the weekly cluster headache attack frequency.
6.2.2. Other Secondary Objectives

To assess whether LY2951742 is superior to placebo on the following:
a.
The proportion of patients with a 50% or greater reduction in the weekly 
number of cluster headache attacks from baseline for each weekly interval 
through Week 8
b.
The proportion of patients with a 30% or greater reduction in the weekly 
number of cluster headache attacks from baseline for each weekly interval 
through Week 8
c.
Mean change in the weekly cluster headache attack frequency from 
baseline for each weekly interval through Week 8
d.
Proportion of patients reporting a score of 1 (“very much better”) or 2 
(“much better”) on the Patient Global Impression of Improvement (PGI-I) 
at Week 4 and Week 8.

To compare the safety and tolerability of LY2951742 with placebo in patients 
with episodic cluster headache using the following measures:
a.
spontaneously reported TEAEs
b.
SAEs
c.
discontinuation rates
d.
suicidal ideation and behaviors assessed by solicited questioning using the 
Columbia-Suicide Severity Rating Scale (C-SSRS)


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LY2951742

To assess the development and consequences of anti-drug antibodies (ADA) to 
LY2951742 in patients exposed to LY2951742; to provide samples for 
subsequent evaluation of neutralizing ADA (NAb).

To evaluate the pharmacokinetics of LY2951742.
6.3.
Exploratory Objectives
To assess whether LY2951742 is superior to placebo as measured by:

Mean change in the weekly number of times an abortive medication was taken 
from baseline for each weekly interval through Week 8 comparing LY2951742 
with placebo.

Change in percentage of times using oxygen from baseline for each weekly 
interval through Week 8 comparing LY2951742 with placebo.

Change in percentage of times using  triptan from baseline for each weekly 
interval through Week 8 comparing LY2951742 with placebo.

Change in percentage of times of using acetaminophen/paracetamol or NSAIDs 
from baseline for each weekly interval through Week 8 comparing LY2951742 
with placebo.

The proportion of patients with a 75% or greater reduction in the weekly number 
of cluster headache attacks from baseline for each weekly interval through 
Week 8 comparing LY2951742 with placebo.  

The proportion of patients with a 100% reduction in the weekly number of cluster 
headache attacks from baseline for each weekly interval through Week 8
comparing LY2951742 with placebo.  

Mean change in the cluster headache attack average weekly pain severity (based 
on 5-point scale) from baseline through Week 8 comparing LY2951742 with 
placebo.
CCI


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LY2951742
7. Investigational Plan
7.1.
Summary of Study Design
Study CGAL is a Phase 3 multi-center, outpatient, randomized, double-blind, placebo-controlled 
study of LY2951742 300 mg in the prevention of episodic cluster headache.  The study has 4
study phases (SP): SP I (screening/washout), SP II (pre-randomization diary), SP III 
(randomized, double-blind, placebo-controlled treatment), and SP IV (post-treatment follow-up)
(Figure CGAL.1).  Patients who discontinue the study during the double-blind treatment phase 
should enter the post-treatment follow-up phase.
Abbreviations:  ePRO = electronic patient reported outcomes; SP = study phase.
X = injection of investigational product
a ePRO diary will be completed daily during SP II and SP III. “Day” will be defined on a 24-hour clock 
day.
b   SP II begins on the day that the patient first records a cluster headache attack in their ePRO diary.
c For patients who entered SP I while in remission, Visit 2 will occur during SP II, and the minimum 
time between Visit 2 and Visit 3 is five days.
d   Telephone visit 7 days after office visit is only for assessment of spontaneously reported adverse 
events.
Figure CGAL.1.
Illustration of study design for clinical protocol I5Q-MC-CGAL.
SP II
Pre-
Randomization 
Diary
Month                  
0
1
Dosing
X        
X         
LY2951742 300 mg
Placebo
ePRO Diary recordinga
4
SP I
Screening
SP III
Treatment
6
First Diary 
Entryb
Randomization
2
SP IV
Post-Treatment Follow-up
Visit        1               
2c
3
5
7    
9
4d
8       
6d


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LY2951742
Study Phase I is the screening/washout phase starting at Visit 1 to the start of SP II and lasting 
for a minimum of 0 days to a maximum of 12 months.  Patients will sign an informed consent 
document at Visit 1 prior to completing study-related initial screening procedures.  For those 
patients who meet initial screening criteria, an electronic patient reported outcome (ePRO) diary 
will be dispensed during SP I to the patient.  Patients will be instructed on how to use the ePRO 
diary to record daily cluster headache attack information and use of allowed abortive treatments
(collectively referred to as ‘daily cluster headache attack information’ throughout the protocol).  
Visit 1 will be considered complete when the last scheduled procedure of the screening
assessment for the patient is completed.
Below is a description of patient flow through SP I and SP II.  Patients can enter into SP I in one 
of two clinical states:  (1) remission; or (2) while in an active cluster period (see inclusion 
criteria #3 and #4):
(1) Patients who enter SP I while in remission
These patients will complete SP I screening procedures at Visit 1 and remain in SP I until 
the onset of their next cluster period.  The patient will begin recording in the ePRO diary 
on the day of their first cluster headache attack (which marks the start of SP II) and 
continue to record in the diary on a daily basis whether or not an attack was experienced 
on a given day.  At the onset of this cluster period, the patient must contact their 
investigator to schedule a Visit 2 and Visit 3.  The minimum time between Visit 2 and 
Visit 3 is five days to allow for laboratory and diagnostic screening test results to be 
completed and reviewed.  At Visit 2, laboratory samples will be collected, and other 
additional baseline procedures will be performed to determine further eligibility (see 
Study Schedule, Attachment 1). As stated above, the investigator needs to ensure 
appropriate washout of excluded medications has occurred before patients begin 
recording their baseline cluster headache attack data and enter SP II.
(2) Patients who enter SP I while in an active cluster headache period
These patients who meet initial screening eligibility can move directly into SP II (the 
baseline phase) as long as they do not need to wash out of any excluded medications. 
Following informed consent, the Visit 1 and Visit 2 procedures are completed at the 
initial visit (Visit 1).
For all patients, SP II begins on the day that the patient first records a cluster headache attack in 
their ePRO diary. The minimum duration of SP II is 10 days of daily ePRO diary recording prior 
to Visit 3, and the preferred maximum duration of SP II is 14 days of daily ePRO diary recording 
prior to Visit 3.  Therefore, sites may schedule Visit 3 beginning 11days from the start of SP II.
Beginning eleven days after the start of SP II, an eligibility report will be available from the 
ePRO vendor for the investigative site personnel to execute that will determine the patient’s 
eligibility based on the patient’s ePRO data from SP II (sites should refer to the study tool:  
“Eligibility Determination and Randomization Process” for the full description of valid dates to 


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LY2951742
execute the eligibility report).  If the patient is eligible, a blinded randomization authorization
code will be listed for the patient. The site personnel, either blinded or unblinded, must log into 
the Eli Lilly Interactive Web Response System (IWRS) to process the patient’s randomization 
visit (Visit 3).  The site should discontinue the non-eligible patient in the IWRS system at Visit 
3.  For patients that are eligible for randomization, the site should enter the randomization 
authorization code provided by the vendor.
Only the Unblinded Site Personnel should confirm the assigned packages in IWRS. The
Unblinded Site Personnel should store the randomization authorization code from the vendor for
each patient in a secure pharmacy record for the study.
SP III is an 8-week randomized, double-blind, placebo-controlled treatment phase.  Patients who 
meet all eligibility criteria will be randomized to LY2951742 300 mg or placebo. The unblinded 
site personnel will prepare the IP for each patient. Each dose of IP will be administered as 3 SC
injections at office visits Visit 3 and Visit 5. After the first administration of IP at V3, the patient 
should remain in the office for 30 minutes for observation. The site will have a scheduled phone 
visit (Visit 4 and Visit 6) with the patient approximately one week after each IP administration to 
collect spontaneously reported AEs.  During SP III, the patient will continue to record their 
cluster headache attack information daily in the ePRO diary.
Study Phase IV is a 16-week post-treatment phase for safety follow-up. Patients who 
discontinue early in SP III should enter the post-treatment phase (SP IV).
7.2.
Discussion of Design and Control
This study is a double-blind, placebo-controlled, multi-center study consisting of 4 study phases: 
a screening/washout phase, a pre-randomization diary phase to assess cluster headache attack 
frequency, a double-blind, placebo-controlled treatment phase to assess treatment outcomes, and 
a post-treatment phase to allow for safety monitoring after LY2951742 treatment is stopped.
The proposed duration of the double-blind treatment phase is 8 weeks, with the primary endpoint 
assessed across Weeks 1 to 3 after the first IP dose.  While Eli Lilly and Company (Lilly)
considers an effect, if present, will be observed after one administration, it is possible one dose 
may not be sufficient for some patients.  Inclusion of a placebo-control for another month 
(following the second IP injection) will allow for the assessment of the efficacy of LY2951742 
through 8 weeks. This duration and use of placebo-control is consistent with current published 
International Headache Society guidelines (IHS 1995), in which a duration of at least 2 weeks is 
recommended when assessing prophylaxis treatment.
The study will allow the use of certain abortive treatments (those initiated at the start of a cluster 
headache attack to shorten overall attack duration) for cluster headache attacks, but will require 
exclusion of all preventive therapies to directly assess the superiority of LY2951742 over 
placebo as a preventive treatment.


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LY2951742
8. Study Population
All patients must meet the following selection criteria.  Eligibility of patients for study 
enrollment will be based on the results of a screening medical history, physical examination, 
clinical laboratory tests, ECG, and cluster headache history during SP I and SP II, as described in 
the Inclusion and Exclusion Criteria sections below.  The nature of any co-morbid conditions 
present at the time of the physical examination and any pre-existing conditions must be 
documented.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
considered for rescreen once, for selected criteria, with approval from Lilly Medical (See Section 
8.3).  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
8.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria:
1. Male and female outpatients 18 to 65 years of age inclusive prior to signing 
informed consent.  
2. At Visit 1, patients must have a history of episodic cluster headache and 
distinguished from chronic cluster headache as defined by IHS ICHD-3 beta
(ICHD-3 2013) (see Section 8.1.1).
3. At Visit 1, have a prior history of a cluster period lasting 6 weeks or greater.
4. At Visit 1, for patients currently in an active cluster period:
a.
In opinion of investigator, would be expected to continue in the current 
period for at least another 6 weeks based on previous cluster period 
history.
b. They are not taking any excluded medications that require washout (see 
Criteria #9).
Note:  patients not meeting criteria a and b must be a screen fail, but they may be 
considered for rescreening.
5. Do not share this inclusion criteria with potential patients: During SP II, 
have a baseline weekly cluster headache attack frequency (based on ePRO 
vendor eligibility report) preceding Visit 3 of:
a.
minimum of 1 cluster headache attack every other day and at least 4 
total attacks
b. maximum of 8 cluster headache attacks per day.
Note:  a patient with 2 or more consecutive days without an attack during the baseline 
assessment will be excluded.


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6. At Visit 1, are able to distinguish cluster headache attacks from other 
headaches (i.e. tension-type headaches, migraine).
7. Investigator judges the patient as reliable to follow all study procedures, keep 
all study visits, and be compliant with study requirements.
8. Women of child-bearing potential may participate in the study.
a.
Women of child-bearing potential must test negative for pregnancy 
(based on a serum pregnancy test) at the time of enrollment and must 
agree to use a reliable method of birth control during the study and for 
5 months following the last dose of investigational product.
b. Male patients agree to use a reliable method of birth control during the 
study and for 5 months following last dose of investigational product.
c.
Women not of child-bearing potential are those who are infertile due 
to surgical sterilization (at least 6 weeks after surgical bilateral 
oophorectomy with or without hysterectomy or at least 6 weeks after 
tubal ligation) confirmed by medical history, or menopause.
Menopause is defined as spontaneous amenorrhea for at least 12 
months not induced by a medical condition, or spontaneous 
amenorrhea of 6 to 12 months and a follicle stimulating hormone 
(FSH) level >40 mIU/mL.
9. Have not taken any of the following excluded medications or other treatments 
for cluster headache within the time frame noted:
a.
use within 14 days prior to SP II of any of the following:
dihydroergotamine or ergot derivatives; gabapentin; lithium; 
melatonin; methergine; topiramate; valproate; verapamil, opioids
b. use within 30 days prior to SP II of any of the following:  systemic or 
injected corticosteroids; occipital nerve block; any other cranial or 
extracranial nerve block; any neurostimulation treatment.
Note:  Patients are allowed to use only the following for acute/abortive treatment for their
cluster headache attacks:  high-flow oxygen; oral triptans, sumatriptan subcutaneous 
injection; sumatriptan nasal spray; zolmitriptan nasal spray; acetaminophen and NSAIDs.
10. Throughout the study (Informed Consent through Visit 9), 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), LSD and 2-bromo-LSD.
11. Agree not to post any personal medical data related to the study or 
information related to the study on any website or social media site (for 
example, Facebook, Twitter, LinkedIn, Google+, etc.) until the entire trial has 
completed.
12. Have given written informed consent.


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8.1.1. Disease Diagnostic Criteria
The planned patient population includes adult outpatients (18 to 65 years of age inclusive) who 
meet the International Headache Society’s International Classification of Headache Disorders, 
Third Edition, beta version (IHS ICHD-3-beta), diagnostic criteria for Episodic Cluster 
Headache (as shown below).
ICHD-3 beta diagnostic criteria for Cluster Headache:
A. At least five attacks fulfilling criteria B–D
B. Severe or very severe unilateral orbital, supraorbital and/or temporal pain lasting 15 to 
180 minutes (when untreated)*
C. Either or both of the following:
1. at least one of the following symptoms or signs, ipsilateral to the headache: (a) 
conjunctival injection and/or lacrimation; (b) nasal congestion and/or rhinorrhea; (c) 
eyelid oedema; (d) forehead and facial sweating; (e) forehead and facial flushing; (f) 
sensation of fullness in the ear; (g) miosis and/or ptosis,
2. a sense of restlessness or agitation.
D. Attacks have a frequency between one every other day and eight per day for more than 
half of the time when the disorder is active
E. Not better accounted for by another ICHD-3 diagnosis.
* During part (but less than half) of the time-course of cluster headache, attacks may 
be less severe and/or of shorter or longer duration.
ICHD-3 beta diagnostic criteria for Episodic Cluster Headache:
A. Attacks fulfilling criteria for Cluster Headache and occurring in bouts (cluster periods)
B. At least two cluster periods lasting from 7 days to 1 year (when untreated) and separated 
by pain-free remission periods of ≥1 month.
8.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria:
13. Current enrollment in, or discontinuation within the last 30 days prior to Visit 
1 from, a clinical trial involving any investigational drug or device, or 
concurrent enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study.
14. Current use or any prior exposure to any CGRP antibody (including 
LY2951742), any antibody to the CGRP receptor, or antibody to nerve growth 
factor (NGF) including past participation in a clinical trial investigating 
CGRP, CGRP receptor, or NGF antibodies.
15. Patients who are taking other therapeutic antibodies or are expected to take 
during the course of the study (for example, adalimumab, infliximab, 
trastuzumab, bevacizumab, etc.). Prior use of other therapeutic antibodies is 
allowed if an adequate wash-out has occurred (≥5 half-lives) prior to SP II.


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16. Any of the following headache-related or pain-related conditions are 
exclusionary:
a.
Current diagnosis of Medication Overuse Headache as defined by 
ICHD-3 beta within 3 months prior to Visit 3.  Note:  daily triptan use 
for daily cluster headache attacks is allowed provided it is not resulting 
in an MOH of some other headache type.
b. 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.
c.
Are taking indomethacin and/or are suspected of having another 
distinct trigeminal autonomic cephalalgia such as hemicrania continua, 
paroxysmal hemicrania, or short-lasting unilateral neuralgiform 
headache attacks (SUNCT or SUNA).
d. Have other significant pain problem that might confound the study 
assessments in the opinion of the investigator.
17. Patients who have taken botulinum toxin type A or B, that was administered 
in the head or neck area, within 4 months of SP II for treatment of cluster 
headache or other disorders, or for cosmetic use.
18. Any (lifetime) history of deep brain stimulation.
19. Evidence of significant active or unstable psychiatric disease by medical 
history, such as bipolar disorder, schizophrenia, personality disorders, or other 
serious mood or anxiety disorders.  
Note: Patients with major depressive disorder 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).
20. Are considered by the investigator to be at significant risk for suicide.
21. Women who are pregnant or nursing.
22. Any of the following cardiovascular-related conditions are exclusionary:
a.
Prior to Visit 3 (randomization), have ECGs showing acute 
abnormalities of:
i. evidence of delayed ventricular repolarization including but not 
limited to a corrected QT (Bazett’s QT interval [QTcB]) 
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


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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).
b. History of myocardial infarction (MI), unstable angina (UA), 
percutaneous coronary intervention, coronary artery bypass graft, or 
deep vein thrombosis/pulmonary embolism within 6 months of 
screening, or have planned cardiovascular surgery or percutaneous 
coronary angioplasty.
c.
Any lifetime history of vasospastic angina or stroke, or recent history 
(6 months) of emergency room visit for chest pain in which an 
ischemic or cardiac event was not ruled out.
d. Clinical evidence of peripheral vascular disease (e.g., Buerger’s 
Disease) or a diagnosis of 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 Visit 3.
23. 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 Visit 3, patients with an elevation of ≥2X the upper limit of 
normal (ULN) for alanine aminotransferase (ALT), or ≥1.5X ULN for 
total bilirubin (TBL) or alkaline phosphatase (ALP) may be retested.  
The patient’s results must be discussed and judged not clinically 
significant by Lilly Medical prior to enrollment.
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.
24. Any of the following drug- or alcohol-related conditions are exclusionary:
a.
Patients who do not agree to abstain from alcohol consumption during 
SP II and SP III of the study.  However, patients are encouraged to 
abstain from alcohol consumption throughout the entire study.


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b. History of drug, alcohol, opioid, or barbiturate abuse/dependence 
within 1 year prior to SP II (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.
c.
History of use of psilocybin (mushrooms), LSD, or 2-bromo-LSD 
within 2 months prior to SP II.
d. Have a positive urine drug screen (UDS) for any substances of abuse 
prior to randomization. Note: One retest may be performed if the 
UDS is positive for any prescribed substance or if, in the judgment of 
the investigator, there is an acceptable explanation for the positive 
result.  The results of the retest must be negative at or prior to Visit 3.
25. Completion of less than 5 of 7 days of the daily ePRO diary entries during the
baseline assessment (defined in Statistical Methods, Section 12) as evidence 
of inadequate compliance.
26. 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.
27. Known hypersensitivity to multiple drugs, monoclonal antibodies or other 
therapeutic proteins, or to LY2951742 or to any of the inactive ingredients
28. Patients with a body mass index (BMI) ≥40 kg/m2.
8.2.1. Rationale for Exclusion of Certain Study Candidates
Exclusion Criterion 13 excludes patients using drugs that cannot be mapped to a standard drug 
dictionary, or for which little data are known to analyze the potential relationship of AEs or drug 
interactions.  Exclusion Criterion 14 eliminates patients who have been exposed to LY2951742, 
NGF, any CGRP antibody, and any CGRP receptor antibody and could induce a potential bias or 
compromise interpretation or integrity of the data.  Exclusion Criteria 15, 16, 19 through 23, 27, 
and 28 are for excluding patients with significant illnesses or conditions that may affect their 
safety or confound study results. Exclusion criteria 17 and 18 exclude patients with current or 
prior therapies that could negatively impact the safety of the patient or influence the analysis of 
the results. Exclusion Criterion 24 excludes treatments or illicit substances that may impact 
study results.  Exclusion Criterion 25 ensures that patients are able and willing to follow the 
protocol schedules and procedures.  Exclusion Criterion 26 prevents conflict of interest in study 
patients.  
8.3.
Rescreening
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:


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
Inclusion Criterion 1; if patients are less than age 18 at time of informed consent, they 
may be rescreened if they reach age 18 during study enrollment.

Inclusion Criterion 4

Inclusion Criterion 5; If a patient fails eligibility due solely to the eligibility report not 
being executed within the required time frames, the patient may be considered for 
rescreen during their next cluster headache period. Rescreening during the current 
cluster headache period is not allowed.

Inclusion Criterion 5b; If a patient fails eligibility due to the occurrence of >8 cluster 
headache attacks per day, the patient may be considered for rescreen during their current 
cluster headache period, if, in the opinion of the investigator, the patient would be 
expected to continue in the current period for at least another 6 weeks based on previous 
cluster period history.  If the patient is not expected to continue in the current period for 
another 6 weeks, the patient may be considered for rescreen during their next cluster 
headache period.

Inclusion Criterion 5 “Note” section only;  a patient with 2 or more consecutive days 
without an attack during the baseline assessment may be considered for rescreen during 
their next cluster headache period.  Rescreening during the current cluster headache 
period is not allowed.  

Inclusion Criterion 9

Exclusion Criterion 13

Exclusion Criterion 15; patients with inadequate washout may be rescreened following 
an appropriate washout period.

Exclusion Criterion 17

Exclusion Criterion 20; 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 Criterion 21

Exclusion Criterion 22f; 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 SP II.

Exclusion Criterion 24d; If a patient fails eligibility due to a positive UDS, the patient 
may be considered for rescreen during their current cluster headache period, if, in the 
opinion of the investigator, the patient would be expected to continue in the current 
period for at least another 6 weeks based on previous cluster period history.  If the 
patient is not expected to continue in the current period for another 6 weeks, the patient 
may be considered for rescreen during their next cluster headache period.

Exclusion Criterion 28


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
Patients using a concomitant medication that requires a stable dose for a specific 
duration prior to SPII per study requirements, may be rescreened if additional time is 
needed to meet the duration requirement.

Patients using concomitant medication(s) that require a wash-out prior to SPII, may be 
rescreened once an adequate wash-out (e.g. 5 half-lives) has occurred.
Additionally, if a patient enters SP I while in remission and does not enter a cluster period during 
the maximum duration of SP I (12 months), they are considered a screen failure and must be 
discontinued from the study. If they still wish to participate in the study and the study is still 
actively enrolling new patients, the individual must sign a new informed consent form (ICF) and 
will be assigned a new identification number and complete Visit 1 again. If a patient enters SP I 
while in remission and the study completes full enrollment while the patient is still in SP I, the 
patient will be discontinued from the study.
The interval between screening and rescreening must be sufficient to meet the required specified 
timeframes in the inclusion/exclusion criteria or concomitant medication list.  If rescreening is 
performed, the individual must sign a new ICF and will be assigned a new identification number.
8.4.
Discontinuations
8.4.1. Discontinuation of Inadvertently Enrolled Patients
The criteria for enrollment must be followed explicitly.  If the investigator site identifies a patient 
who did not meet enrollment criteria and who was inadvertently enrolled, the sponsor must be 
notified.  If the sponsor identifies a patient who did not meet enrollment criteria and who was 
inadvertently enrolled, the investigator site will be notified.  A discussion must occur between 
the sponsor clinical research physician (CRP) and the investigator to determine whether the 
patient may continue in the study, with or without IP.  Inadvertently enrolled patients may be 
maintained in the study and on IP when the Lilly CRP agrees with the investigator that it is 
medically appropriate for that patient.  The patient may not continue in the study with or without
IP if the Lilly CRP does not agree with the investigator’s determination it is medically 
appropriate for the patient to continue.  The investigator must obtain documented approval from 
the Lilly CRP to allow the inadvertently enrolled patient to continue in the study with or without 
IP.  The decision of whether to allow an inadvertently enrolled patient to continue in the study, 
with or without IP, will be documented in the study issues and decisions log.
8.4.2. Discontinuation of Investigational Product
Discontinuation of the IP for abnormal liver tests should be considered by the investigator when 
a patient meets one of the following conditions after consultation with the Lilly designated 
medical monitor:

ALT or AST >8ULN

ALT or AST >5ULN for more than 2 weeks

ALT or AST >3ULN and either TBL level >2ULN or international 
normalized ratio (INR) >1.5ULN


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
ALT or AST >3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 
one of the following criteria and is deemed to be of liver origin and drug related:  

ALP >3ULN

ALP >2.5ULN and TBL >2ULN

ALP >2.5ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%).  
Patients who discontinue the IP early should discontinue from SP III and enter SP IV, the post-
treatment phase.  If the patient refuses to enter the post-treatment follow-up phase, they will have
end-of-therapy procedures performed as shown in the Study Schedule (Attachment 1).  
8.4.3. Patient Discontinuation from the Study
All patients are free to withdraw from participation in this study at any time and for whatever 
reason, specified or unspecified, and without prejudice.
A patient may be discontinued from the study for any of the following reasons:

If a patient remains within the screening phase when study enrollment is complete, the 
patient will be discontinued.

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.

Investigator Decision
o
the investigator decides that the patient should be discontinued from the study
o
if the patient, for any reason, requires treatment with another therapeutic agent, 
between 30 days prior to SP II through SP III, for the prevention of cluster 
headache, the investigator must discontinue that patient from the study prior to 
introduction of the new agent

Subject Decision 
o
the patient requests to be withdrawn from the study

Sponsor Decision
o
Lilly or its designee stops the study or stops the patient’s participation in the study 
for medical, safety, regulatory, or other reasons consistent with applicable laws, 
regulations, and good clinical practice (GCP)

Adverse Event 


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o
If the investigator decides that the patient should be withdrawn because of an 
SAE or a clinically significant laboratory value, the IP is to be discontinued and 
appropriate measures are to be taken.  Lilly or its designee is to be alerted 
immediately.  Refer to Safety Evaluations Section 10.2.
Patients who discontinue the study early during SP III should enter the post-treatment period; 
those patients who discontinue the study early during SP IV will have end-of-study procedures 
performed as shown in the Study Schedule (Attachment 1).
8.4.4. Patients Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.
8.4.5. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the 
ethical review board (ERB) of the study site judges it necessary for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and GCP.
8.4.6. Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.


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9. Treatment
9.1.
Treatments Administered
This study includes 2 treatment groups:  placebo or LY2951742 300 mg.  Each treatment group 
will be administered three 1 ml SC injections, by qualified site personnel, every 30 days for a 
total of 2 administrations during SP III.  The designated unblinded site personnel responsible for 
preparing LY2951742 and placebo doses should refer to the Pharmacy Binder Dosing 
Instructions for LY2951742 Drug Product, 75 mg, for the preparation and dosing instructions for 
both LY2951742 and placebo.
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, and

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 IP so that the situation can be assessed.
9.2.
Materials and Supplies
LY2951742 for Injection, 75 mg, will be supplied by the sponsor as a lyophilized formulation in 
a glass vial.  The drug product is composed of the active ingredient, LY2951742, in citrate buffer 
in addition to other inactive ingredients.
Details for the requirements for preparation of the LY2951742 doses and placebo solutions will 
be provided to the unblinded site personnel in the Pharmacy Binder Dosing Instructions for 
LY2951742, 75 mg.
Storage and Stability
Unreconstituted glass vials of LY2951742 for Injection, 75 mg, are stable and must be stored in a 
refrigerator at 2ºC to 8ºC (35.6ºF to 46.4ºF).
Approximately 20 minutes prior to preparing for administration to patients, the vials should be 
removed from the 2°C to 8°C storage area and allowed to equilibrate at ambient conditions.  
After dose preparation, immediate transfer to the syringe is recommended for administration.  
Drug product must be administered within 6 hours when stored at room temperature.
Investigational Product Dose Preparation


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The designated unblinded site personnel is responsible for preparing LY2951742 and placebo 
injections according to the CGAL Pharmacy Binder Dosing Instructions for LY2951742, 75 mg, 
and each dose will be identified as study drug without identification of the drug or dose. 
Individuals involved with study drug preparation will not be involved in any clinical aspects of
the study, including study drug administration, clinical evaluations, and AE assessments.  
Following dose preparation, the unblinded site personnel should complete the overlay label and 
apply onto the prepared syringes prior to providing the syringes to the blinded site personnel.
9.3.
Method of Assignment to Treatment
A patient number will be assigned to each patient after the ICF is signed and dated. This
identification number must appear on all patient-related documents.
Patients who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 3.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an IWRS. The IWRS will be used to assign double-blind investigational product 
to each patient. The Unblinded Site Personnel should confirm the assigned packages in IWRS
prior to preparation and administration.
The IWRS system will be programed following the dynamic allocation (minimization) method of 
Pocock and Simon (1975) to balance the treatment arms for the factors of gender, average daily 
attack frequency (≤4 attacks per day, >4 attacks per day) and investigative site.  The purpose of 
the algorithm is to maintain approximately the same proportion of gender and baseline average 
daily attack frequency in each arm of the study, and to balance (based on the treatment allocation 
ratio) the number of patients assigned to treatment arms within each investigative site.
9.4.
Rationale for Selection of Doses in the Study
The dose level proposed for the study of LY2951742 in cluster headache is 300 mg administered 
approximately every 30 days.  Based on inhibition of capsaicin-induced dermal blood flow 
(CIDBF) and 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 (about 90% decrease in unbound plasma CGRP concentrations; >ED90 based on 
CIDBF), and be sufficient to test the effectiveness of LY2951742 for the treatment of cluster 
headache.  A dose of 300 mg every 30 days is predicted to replicate the exposure and have the 
same effect on CIDBF and unbound plasma CGRP as 150 mg Q2W, which yielded evidence of 
efficacy in migraine (Study ART-01).  The safety and tolerability of LY2951742 supports dosing 
at 300 mg every 30 days.
9.5.
Selection and Timing of Doses
Patients in this study will be assigned to 1 of 2 treatment groups:  placebo or LY2951742 300 
mg. Investigational product (LY2951742 or placebo) will be administered as three 1-mL SC
injections every 30 days for a total of 2 administrations during SP III.  Investigational product
injections should be administered after all other study procedures are completed for the given 
visit.


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9.6.
Continued Access to Investigational Product
LY2951742 will not be made available to patients after conclusion of the study.
9.7.
Blinding
This is a double-blind study.  To preserve the blinding of the study, only a minimum number of 
Lilly personnel will see the randomization table and treatment assignments before the study is 
complete.
After the reporting database is locked for statistical analysis of the double-blind treatment phase, 
a limited number of sponsor personnel will be unblinded to complete the study report and 
prepare for regulatory submission.  However, any sponsor personnel continuing with the 
management and oversight of the trial will remain blinded to patients’ previous treatment 
assignment.
Emergency unblinding for AEs may be performed through the IWRS.  This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment.  All 
unblinding events are recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study.  In cases where there are ethical reasons to have the patient 
remain in the study, the investigator must obtain specific approval from a Lilly CRP for the 
patient to continue in the study.
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted.  Patient safety must always be the first 
consideration in making such a determination. If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly CRP prior to unblinding 
a patient’s treatment assignment.  If a patient’s treatment assignment is unblinded, Lilly must be 
notified immediately.
9.8.
Concomitant Therapy
Patients will be allowed to use only the following acute/abortive treatments for their cluster 
headache attacks: high-flow oxygen; oral triptans, sumatriptan SC injections; sumatriptan nasal 
spray; zolmitriptan nasal spray; acetaminophen; NSAIDs.  No medications, treatments, 
procedures, or other interventions for the preventive treatment of cluster headache are permitted
during SP II and SP III. In SP IV, if the investigator deems it necessary to resume a preventive 
medication for a patient, the patient is allowed to resume only the following medications for 
prevention of cluster headache:  verapamil (maximum daily dosage:  480 mg), lithium, 
melatonin, valproate, gabapentin, and topiramate. Patients will be asked to record use of their 
allowed standard abortive treatments in their daily ePRO diary.
A list of allowed/not allowed medications will be provided separately.  Site personnel should 
call a designated Lilly representative with any questions regarding medications not specifically 
cited in the list of allowed/not allowed medications. Any changes in the list of allowed/not 


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allowed medications will be communicated to investigators and will not constitute a protocol 
amendment.
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 
CRP/CRS or delegate.


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10.
Efficacy, Safety Evaluations, Sample Collection and 
Testing, and Appropriateness of Measurements
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule (Attachment 1).
10.1. Efficacy Measures
10.1.1. Primary Efficacy Measure
ePRO Diary: Patients will be asked to record the number of cluster headache attacks in their 
daily ePRO diary during SP II and SP III.  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 (Sumatriptan Cluster Headache Study Group 1991).  
Patients should record all cluster attacks regardless of attack duration.
10.1.2. Secondary Efficacy Measure
The Patient Global Impression of Improvement 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).
10.2. Safety Evaluations
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.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious, considered related to the study treatment or the study, or that caused the
patient to discontinue before completing the study.  The patient should be followed until the 
event is resolved or explained.  Frequency of follow-up evaluation is left to the discretion of the 
investigator.
10.2.1. Adverse Events
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish drug effect.
Cases of pregnancy that occur during maternal or paternal exposures to investigational product 
should be reported.  Data on fetal outcome and breast-feeding are collected for regulatory 
reporting and drug safety evaluation.


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Study site personnel will record 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.
After the informed consent form (ICF) is signed, site personnel will record any change in the 
condition(s) and the occurrence and nature of any AEs.  All AEs related to protocol procedures 
are reported to Lilly or designee via eCRF into the Lilly designated electronic data capture 
system (EDC).
In addition, all AEs occurring after the patient receives the first dose of investigational product 
must be reported to Lilly or its designee via eCRF.
Any clinically significant findings from ECGs, laboratory measurements, vital sign 
measurements, other procedures, and so on that result in a diagnosis should be reported to Lilly 
or its designee using eCRF.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, cluster headache, IP, using eCRF.
The investigator decides whether he or she interprets the observed AEs as either related to 
disease, to the study medication, study procedure, or other concomitant treatment or pathologies.  
To assess the relationship of the AE to the IP, the following terminologies are defined:

Related:  a direct cause and effect relationship between the study treatment and 
the AE is likely.

Possibly related:  a cause and effect relationship between the study treatment and 
the AE has not been demonstrated at this time and is not probable, but is also not 
impossible.

Unrelated:  without question, the AE is definitely not associated with the study 
treatment.
For analytical purposes only, according to Lilly’s standard operating procedures all “related” and 
“possibly related” AEs and SAEs will be defined as related to the IP.
10.2.1.1. Serious Adverse Events
Serious adverse event collection begins after the patient has signed informed consent and has 
received investigational product.  If a patient experiences an SAE after signing informed consent, 
but prior to receiving investigational product, the event will NOT be reported as serious unless 
the investigator feels the event may have been caused by a protocol procedure.
Planned surgeries should not be reported as SAEs unless the underlying medical condition has 
worsened during the course of the study.
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.  


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An SAE is any AE from this study that results in one 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 adverse drug events when, based upon appropriate 
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse events occurring up to and including the patient’s last study visit will be 
collected, regardless of the investigator’s opinion of causation, in the clinical data collection 
database and the pharmacovigilance system at the sponsor.
The investigator does not need to actively monitor patients for adverse events once the trial has 
ended, unless provided otherwise in the protocol.  However, if an investigator becomes aware of
SAEs occurring to a patient after the patient’s participation in the trial has ended, the investigator 
should report the SAEs to the sponsor, regardless of the investigator’s opinion of causation, and 
the SAEs will be entered in the pharmacovigilance system at the sponsor.
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 trial may be 
found in the IB.
10.2.1.1.1.Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the recording 
and expedited reporting of SUSARs that are consistent with global regulations and the associated 
detailed guidances.
10.2.2. Other Safety Measures
10.2.2.1. Electrocardiograms
For each patient, 12-lead digital ECGs will be collected according to the Study Schedule 
(Attachment 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 may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high quality records.


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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 patient meets entry criteria and for immediate 
subject management, should any clinically relevant findings be identified.
After enrollment, if a clinically significant increase in the QT/corrected QT (QTc) interval from 
baseline, or other clinically significant quantitative or qualitative change from baseline, is 
present, the investigator will assess the patient for symptoms (for example, palpitations, near 
syncope, syncope) and to determine if the patient can continue in the study. The investigator or 
qualified designee is responsible for determining if any change in patient management is needed 
and must document his/her review of the ECG printed at the time of evaluation.
All digital ECGs will be electronically transmitted to a designated central ECG laboratory.  A 
cardiologist at the central ECG laboratory will then conduct a full overread on the ECG 
(including all intervals); a report based on data from this analysis will be issued to the 
investigative site. All data from the overreads will be placed in the Lilly database for analytical 
and study report purposes.
When there are differences in ECG interpretation between the investigator (or qualified 
designee) and the cardiologist at the central ECG laboratory, the investigator (or qualified 
designee’s) interpretation will be used for study entry and immediate patient management. 
Interpretations from the cardiologist at the central ECG laboratory will be used for data analysis 
and report writing purposes.
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.
10.2.2.2. Vital Signs
Blood pressure and pulse will be collected in triplicate at every scheduled and unscheduled office 
visit as specified in the Study Schedule (Attachment 1).  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.  


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10.2.2.3. Columbia-Suicide Severity Rating Scale, Self-Harm Supplement Form, 
and Self-Harm Follow-up Form 
The C-SSRS and Self-Harm Supplement Form (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 Study Schedule (Attachment 1).  The C-SSRS 
captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors during 
the assessment period (Posner et al. 2011).  The scale includes suggested questions to solicit the 
type of information needed to determine if a suicide-related thought or behavior occurred.  The 
SHSF captures the number of discrete events of suicidal behavior, possible suicidal behavior, or 
nonsuicidal self-injurious behavior and must be completed at every visit.  Additionally, the Self-
Help Follow-up Form (SHFU) will be completed at any visit, including screening/baseline visits, 
when a suicidal or non-suicidal 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.
10.2.3. Safety Monitoring
The Lilly clinical research physician will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly 
CRP/CRS will, as is appropriate, consult with the functionally independent Global Patient Safety 
(GPS) therapeutic area physician or clinical scientist, and periodically review:

trends in safety data

laboratory analytes 

adverse events including monitoring of injection site reactions, allergic reactions, and 
infections.
If a study patient experiences elevated ALT 3X ULN, ALP 2X ULN or elevated TBL 2X
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 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 (Attachment 3).
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the data monitoring committee (an advisory group for this 
study formed to protect the integrity of data) can conduct additional analyses of the safety data
prior to completion of the double-blind treatment phase.
10.2.4. 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.
For blinded studies, all product complaints associated with material packaged, labeled, and 
released by Lilly or delegate will be reported.


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The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee.
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.3. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study.
Attachment 2 lists the laboratory tests that will be performed for this study.
Attachment 3 lists the selected tests that may be obtained in the event of a treatment-emergent
hepatic abnormality.
Attachment 4 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
10.3.1. Samples for Study Qualification and Health Monitoring
Blood and urine samples will be collected to determine whether patients meet 
Inclusion/Exclusion criteria and to monitor patient health.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run, or to retain the samples until the end of the study to confirm that the results 
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.3.2. Samples for Biomarker Research
Biomarker research is used to address questions of relevance to drug disposition, target 
engagement, pharmacodynamics, mechanism of action, variability of patient response (including 
safety) and clinical outcome.  
Specimen storage is incorporated in clinical trials to enable examination of these questions 
through measurement of biomolecules including deoxyribonucleic acid (DNA), ribonucleic acid
(RNA), proteins, lipids, other cellular elements.  Where local regulations and ERBs allow, these 
samples will be collected for biomarker research as discussed below and specified in the Study 
Schedule (Attachment 1).


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All biomarker samples will be coded with the patient number.  These samples and any data 
generated can be linked back to the patient only by the investigator site personnel.  Samples will 
be destroyed according to a process consistent with local regulations.
10.3.4. Samples for Non-genetic Biomarker Research
Samples will be collected for potential non-pharmacogenetic biomarker research. Plasma 
samples (
 K+/EDTA plasma storage samples) and whole blood RNA
(storage sample) will be collected at the times specified in the Study Schedule (Attachment 1) 
and in the amounts specified (Attachment 4).
Samples may be used for research on the drug target, disease process (specifically including 
cluster headache with its variants and more broadly including pain conditions for which CGRP 
may be relevant), pathways associated with episodic cluster headache, mechanism of action of 
LY2951742, and/or research method or in validating diagnostic tools or assay(s) related to 
episodic cluster headache.
Samples will be retained for a maximum 15 years after the last patient visit for the study at a 
facility selected by the sponsor. This retention period will enable use of new technologies, 
response to regulatory questions, and investigation of variable response that may not be observed 
until later in drug development or when the drug is commercially available.
CCI
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10.3.5. Samples for Immunogenicity Research
Blood samples for immunogenicity testing will be collected to determine antibody production 
(with or without pre-existing antibodies) against LY2951742.  Immunogenicity will be assessed 
by a validated assay designed to detect anti-drug antibodies in the presence of the investigational 
product.  Antibodies may be further characterized and/or evaluated for their ability to neutralize 
the activity of LY2951742.
Samples, including residual aliquots, may be stored for a maximum of 15 years following last 
patient visit for the trial at a facility selected by the sponsor to enable further analysis of immune 
responses to the LY2951742.  The duration allows the sponsor to respond to regulatory requests 
related to the LY2951742.
10.4. Appropriateness of Measurements
All efficacy and safety assessments have been well documented and are generally regarded as
reliable, accurate, and relevant in this patient population.
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11.
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 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.
To ensure the safety of participants in the study, and to ensure accurate, complete, and reliable 
data, the investigator will keep records of ECGs, laboratory tests, clinical notes, and patient 
medical records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable ERBs with 
direct access to original source documents.
11.1. 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.
Some or all of a patient’s data will be directly entered into the eCRF at the time that the 
information is obtained.  In instances, where the data cannot be directly data entered, the site will 
maintain source documentation in the trial files and the patient’s data will be transcribed into the 
eCRF.  Any data for which the eCRF will serve as the source document, or any other data not 
entered directly into the eCRF (for example, ePRO or patient rated outcomes), will be identified 
and documented by site in the site’s trial file.  For data handled by a data management third party 
organization (TPO), eCRF data and some or all data that are related will be managed and stored 
electronically in the TPO system.  Subsequent to the final database lock, validated data will be 
transferred to the sponsor.
For data handled internally, eCRF data and some or all data that are related will be managed by
the sponsor and stored electronically in the sponsor’s system
In this study, patient cluster headache data will be collected directly via an ePRO diary as part of 
an ePRO/COA system. In addition, the patient-rated PGI-I; clinician-rated C-SSRS, SHSF and 
SHFU are collected at office visits as part of the ePRO/COA system.  


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If ePRO/COA records are stored at a third party site, investigator sites will have continuous 
access to the source documents during the study and will receive an archival copy at the end of 
the study for retention.
Any data for which the ePRO/COA instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
Case report form data collected by the TPO will be encoded by the TPO and stored electronically 
in the TPO’s database system.  Validated data will subsequently be transferred to the sponsor 
using standard Lilly file transfer processes.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system.  Data will subsequently be transferred from the central 
vendor to the Lilly generic labs system.  Data from complaint forms submitted to Lilly will be 
encoded and stored in the global product complaint management system.


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12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
The study is planned to have a minimum of approximately 162 patients randomized 1:1 to 
placebo or LY2951742 with the opportunity to increase the final sample size at an interim 
analysis if indicated in order to maintain a well powered study. To preserve blinding, details of 
the sample size and power calculations are omitted from this protocol and are provided in a 
separate document to the ERB.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Unless otherwise specified, efficacy analyses during SP III will be conducted on an intent-to-
treat (ITT) population, which include all patients who are randomized and receive at least 1 dose 
of IP. Patients in the ITT population will be analyzed according to the treatment group to which 
they were randomized.  Safety analyses during SP III will be conducted on the safety population, 
which also includes all patients who were randomized and receive at least 1 dose of study drug.  
However, patients will be analyzed by actual study treatment received most often (modal 
treatment) during the double-blind treatment phase.  When change from baseline is assessed, the 
patient will be included in the analysis only if he/she has a baseline and a post-baseline 
measurement.
For analyses of the post-treatment phase, the post-treatment population will be used.  Post-
treatment population will be defined as all patients who entered the post-treatment phase (SP IV) 
as indicated by entering any post-treatment visit.  
Details related to handling of missing data will be described in the SAP.
Treatment effects will be evaluated based on a 2-sided significance level of 0.05 for all the 
efficacy and safety analyses unless otherwise stated. The 95% confidence intervals (CIs) for the 
difference in least-square means (LSMeans) between treatment groups will be presented. 
Adjustments for multiple comparisons for the analyses corresponding to the primary and gated 
secondary objectives are described in the sections on the primary and secondary efficacy 
analyses below. There will be no adjustments for multiplicity for analyses of other data.
Categorical comparisons between treatment groups will be performed using Fisher’s exact tests, 
where appropriate.
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 changes, will be described 
in the statistical analysis plan (SAP) and/or in the clinical study report.
Additional exploratory analyses of the data will be conducted as deemed appropriate.


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Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.  SAS® software will be used to perform most or all statistical analyses.
12.2.2. 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.
The number and percentage of ITT patients who complete the study or discontinue early will be 
tabulated for both treatment groups for SP III and SP IV both overall and by visit.  Reasons for 
discontinuation will be compared between treatment groups for SP III using Fisher’s exact test.  
Descriptive statistics only will be presented for the treatment groups in SP IV.
12.2.3. Patient Characteristics
The following patient characteristics will be recorded at baseline and will be summarized by 
treatment groups for all ITT patients:

Demographic (age, gender, race, ethnicity, country, region, height, weight, BMI)

Baseline disease characteristics, such as:
o
Number of weekly cluster headache attacks
o
Number of times an abortive medication was taken 
o
Average severity of cluster headache pain 
o
Average cluster headache attack duration 
o
Number of times an abortive medication was taken per cluster headache attack

Baseline alcohol, tobacco, caffeine and nicotine consumption 

Medical history and Pre-existing condition 

Prior cluster headache history in last 7 days of Visit 1.
Comparisons between treatment groups will be performed using Fisher’s exact tests for
categorical data and ANOVA with treatment and pooled investigative site as independent
variables in the model for continuous data.
Medical history and pre-existing conditions will be summarized by preferred term (PT) within 
system organ class (SOC), and comparison between treatment groups will be performed using 
Fisher’s exact test.
12.2.4. Concomitant Therapy
The proportion of patients who received concomitant medication collected from eCRF as well as 
abortive medications for cluster headache attack collected through ePRO will be summarized
separately for all ITT patients for both SP III and SP IV. Treatment group comparisons will be 
done using Fisher’s exact test for SP III with the ITT population.  Descriptive statistics only will 
be presented for the treatment groups in SP IV.
12.2.5. Treatment Compliance
Treatment compliance will be calculated for SP III as:


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number of full doses received ∗100
number of intended full doses
Comparisons between treatments for treatment compliance will be performed using an ANOVA 
with treatment and pooled investigative site in the model.
12.2.6. ePRO Diary Compliance
ePRO diary compliance at each weekly interval (including baseline, Week 1, 2, 3, 4, 5, 6, 7 and 
8) will be calculated.  Diary compliance at each interval is calculated as:
Actual number of diary entry days in the interval ∗100
Expected number of diary entry days in the interval
The diary entry can only be saved and submitted after all the required ePRO questions are 
answered, so the actual number of diary entries represents the total number of days with non-
missing answer to all the required cluster headache attack ePRO questions.  
The expected number of diary entry days is calculated as the (last calendar date - the first 
calendar date in each interval+1).
Comparisons between diary compliance for each interval separately will be performed using an 
ANOVA with treatment and pooled investigative site in the model.
Compliance will also be listed by weekly interval for each patient.
12.2.7. Primary and Gated Outcome and Methodology
12.2.7.1. Primary Outcome
The primary analysis will be conducted by a restricted maximum likelihood-based (REML-
based), mixed-effects repeated measures (MMRM) analysis using all the longitudinal 
observations from Week 1 to Week 3.  The analysis of the primary outcome will be the main 
effect of treatment between LY2951742 300 mg and placebo across Weeks 1 to 3 of the 
treatment phase from a repeated measures analysis on mean change from baseline in the weekly 
attack frequency. This provides the average treatment effect over the 3-week period.  Baseline is 
defined as the last 7 days in the eligibility report (pre-randomization diary phase).
The model for the primary analysis will include the fixed, categorical effects of treatment, 
gender, pooled investigative site, week, and treatment-by-week interaction, as well as the 
continuous, fixed covariates of baseline value.  An unstructured covariance structure will be used 
to model the within-patient errors.  The Kenward-Roger (Kenward and Roger 1997) 
approximation will be used to estimate denominator degrees of freedom.  If the model does not 
converge with both the Hessian and the G matrix being positive definite under the default fitting 
algorithm used by PROC MIXED, the Fisher’s scoring algorithm will be implemented by 
specifying the SCORING option in SAS.  If the model still fails to converge, the model will be 
fit using covariance matrices of the following order specified by a decreasing number of 
covariance parameters until convergence is met:


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
Heterogeneous Toeplitz

Heterogeneous First-order autoregressive 

Toeplitz

First-order autoregressive
If necessary, both the default and the scoring fitting algorithms will be used in the prespecified 
order before proceeding to the next covariance structure in the sequence.  For models where the 
unstructured covariance matrix is not utilized, the sandwich estimator (Diggle and Kenward
1994) will be used to estimate the standard errors of the fixed effects parameters.  The sandwich 
estimator is implemented by specifying the EMPIRICAL option in SAS.  When the sandwich 
estimator is utilized, the Kenward-Roger approximation for denominator degrees of freedom 
cannot be used.  Instead, the denominator degrees of freedom will be partitioned into between-
patient and within-patient portions by the DDFM=BETWITHIN option in SAS.
12.2.7.2. Gated Secondary
The gated secondary outcome, 50% response, is the proportion of patients meeting the response 
criteria at Week 3 and will be assessed using Koch’s Nonparametric Randomization-Based 
Analysis of Covariance method (Koch et al. 1998).  A non-responder imputation for missing 
values will be used.  Specifically, all patients who discontinue study treatment at any time prior 
to Week 3, for any reason, will be considered a non-responder at all missing assessments.
12.2.8. Other Efficacy Analyses 
The secondary and exploratory efficacy analyses will be conducted for SP III.
For the continuous secondary and exploratory efficacy measures, the change from baseline to 
each weekly interval post-baseline measure will be analyzed from repeated measures analyses.
For efficacy measures that are not derived from cluster headache attack frequency, the baseline 
average daily cluster headache attack frequency category (≤4 vs >4) will be added as a covariate 
in the MMRM model. 
For the categorical secondary efficacy measures including 30% response, 50%, and 75% 
response and 100% response, the percentage of patients meeting response criteria at each weekly
interval will be estimated for each treatment from a categorical, pseudo-likelihood-based 
repeated measures analysis of longitudinal binary outcomes indicating whether patients meet 
response criteria.  This analysis will be implemented using the GLIMMIX procedure in SAS.
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12.2.10.
Safety Analyses
The safety analyses will be conducted for SP III and SP IV.
The safety and tolerability of treatment will be assessed by summarizing the following:

AEs
o
TEAEs

By preferred term

By system organ class

By maximum severity 

Considered to be related to IP by investigator
o
SAEs
o
AE leading to discontinuation

Suicidal ideation and behaviors assessed by solicited questioning using the C-SSRS

Vital signs and weight

ECGs

Laboratory measurements

Anti-drug antibody.
12.2.10.1.
Categorical Safety Variables
Unless specified otherwise, the categorical safety analyses will include both schedule and 
unscheduled visits.
Comparisons between treatment groups for all categorical safety measures will be made using 
Fisher’s exact test for SP III with the safety population.  Descriptive statistics only will be 
presented for the treatment groups in SP IV with the post-treatment population.
12.2.10.2.
Adverse Events
Treatment-emergent adverse events (TEAEs) are defined as the reported AEs that first occurred 
or worsened during the post-baseline phase compared with baseline phase.  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 post-
baseline is greater than the maximum baseline severity, the event is considered to be treatment-
emergent for the specific post-baseline period.  For each patient and TEAE, the maximum 
severity for the MedDRA level being displayed (Preferred Term [PT], High Level Term, or 
System Organ Class [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.
12.2.10.3.
Suicide-Related Thoughts and Behaviors
Suicidal ideation, suicidal behavior, and non-suicidal self-injurious behavior based on the 
C-SSRS will be summarized by treatment group.  In particular, for each of the following events, 
the number and percentage of patients with the event will be enumerated by treatment:  


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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 plan) 
without intent to act, non-specific 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 one of various 
composite measures during SP III and SP IV separately will be presented and compared.  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.
Fisher’s exact test will be used for pairwise treatment comparisons.
12.2.10.4.
Vital Signs and Weight
Vital signs collected during the study include systolic and diastolic blood pressure, pulse, and 
temperature.  Blood pressure and pulse measurements will be taken when the patient is in a 
sitting position.  Three measurements of sitting blood pressure and pulse will be collected at 
approximately 30 to 60 second intervals at every visit and those 3 sitting blood pressure and 
pulse measurements will be averaged and used as the value for that visit for analysis.
The incidence rates of patients with treatment-emergent vital sign and weight changes based at 
any time post-baseline will be assessed using Fisher’s exact tests.  Specific criteria for treatment 
emergent definition will be documented in the SAP.
12.2.10.5.
Electrocardiogram Intervals and Heart Rate
Analyses of corrected QT (QTc) and QTcF (measured in milliseconds [msec]) will be calculated 
with Fridericia’s formula as QT/RR⅓.  The number and percent of patients meeting criteria for 
treatment-emergent abnormalities in ECG intervals (pulse rate [PR], QRS, and QTcF) and heart 
rate at any time during study will be summarized.  Treatment group comparisons will be 
performed using Fisher’s exact test.
In addition, descriptive summary of qualitative ECG abnormalities will be conducted which will 
include summaries of 11 ECG categories (Axis, Rhythm, Conduction, Ischemia, Infarction, 
Injury, Morphology, U-waves, T-waves, ST Segment, and Other Abnormalities) of qualitative 
findings at any time post-baseline.
12.2.10.6.
Laboratory Tests
The incidence rates of patients with treatment-emergent abnormal, high, or low laboratory values 
at any time post-baseline will be assessed using Fisher’s exact tests for each laboratory test.
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 post-baseline 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 post-baseline visit.  Patients with all normal or low 


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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 post-baseline visit.  Patients with all normal values at baseline will be 
included in the analysis of treatment-emergent abnormal laboratory values.
12.2.10.7.
Immunogenicity Analyses
Refer to the SAP for details.
12.2.11.
Subgroup Analyses
Refer to the SAP for details.
12.2.12.
Interim Analyses
Up to 2 formal interim analyses are planned for this trial.  The first interim analysis will occur
during SP III which may result in increasing the sample size or stopping the trial for futility.  
Details will be documented in the Statistical Analysis Center SAP, the ERB supplement and the 
Data Monitoring Committee (DMC) Charter.  However, this interim analysis for sample size re-
estimation will not happen due to enrollment infeasibility.  The DMC will still independently 
monitor patient safety during this trial. 
The other interim analysis will be conducted after all patients have completed SP III, and thus, 
will be the final analysis of the primary efficacy endpoint.  This interim analysis will be 
conducted using internal unblinded study team members who do not have direct interaction with 
sites.
Unblinding details are specified in the unblinding plan section of the statistical analysis plan 
(SAP) or a separate unblinding plan document.


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13.
Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including 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.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study, and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring 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.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are used at investigative sites(s).  
All ICFs must be compliant with the International Conference Harmonisation (ICH) guideline on 
GCP.
The investigator must give assurance that the ERB was properly constituted and convened as 
required by 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).  The ERB(s) will review the protocol as required.
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.
13.3. Regulatory Considerations
This study will be conducted in accordance with:
1) consensus ethics principles derived from international ethics guidelines, including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences
(CIOMS) International Ethical Guidelines
2) the ICH GCP Guideline (E6)
3) applicable laws and regulations.
The investigator or designee will promptly submit the protocol to applicable ERB(s).


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Some of the obligations of the sponsor will be assigned to a TPO.
An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Licensed physicians with a specialty including, but not limited to, neurology and headache 
specialists will participate as investigators in this clinical trial.
13.3.2. 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.
13.3.3. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report 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.
The sponsor’s responsible medical officer and statistician will approve the final clinical study 
report for this study, confirming that, to the best of his or her knowledge, the report accurately 
describes the conduct and results of the study.


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14.
References
de Hoon J, Montieth D, Vermeersch S, Van Hecken A, Abu-Raddad E, Collins E, Schuetz T, 
Scherer J, Grayzel D. Safety, pharmacokinetics, and pharmacodynamics of LY2951742: a
monoclonal antibody targeting CGRP [abstract]. In: Abstracts of the 2013 International 
Headache Congress, 27–30 June 2013, John B. Hynes Veterans Memorial, Convention Center, 
Boston, MA, USA. Cephalalgia. 2013:33(Suppl 8);247. Abstract P367.
Diggle P, Kenward MG. Informative drop-out in longitudinal data analysis. J Royal Statist Soc 
Series C: Appl Statist. 1994;43(1):49-93.
Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. Safety and 
efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the 
prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study.  Lancet 
Neurol. 2014:13(9);885-892.
Edvinsson L, Goadsby PJ. Neuropeptides in migraine and cluster headache. Cephalalgia. 
1994;14(5):320-327.
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 December 16, 
2014.
[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.
[IHS] International Headache Society. Guidelines for controlled trials of drugs in cluster 
headache. 1995. Available at: http://www.ihs-headache.org/ichd-guidelines. Accessed 
December 16, 2014.
Karst M, Halpern JH, Bernateck M, Passie T. The non-hallucinogen 2-bromo-lysergic acid 
diethylamide as preventative treatment for cluster headache: an open, non-randomized case 
series. Cephalalgia. 2010;30(9):1140-1144.
Kenward MJ, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53(3):983-997.
Koch GG, Tangen CM, Jung JW, Amara IA. Issues for covariance analysis of dichotomous and 
ordered categorical data from randomized clinical trials and non-parametric strategies for 
addressing them. Stat Med. 1998;17(15-16):1863-1892.
Manzoni GC, Terzano MG, Bono G, Micieli G, Martucci N, Nappi G. Cluster headache—
clinical findings in 180 patients. Cephalalgia. 1983;3(1):21-30.


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Matharu MS, Goadsby PJ. Trigeminal Autonomic Cephalgias. J Neurol Neurosurg Psychiatry. 
2002;72(Suppl 2):ii19-ii26.
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.
McGeeney BE. Hallucinogens and cannabinoids for headache. Headache. 2012;52(Suppl 2):94-
97.
Pocock S, Simon R. Sequential treatment assignment with balancing of prognostic factors in 
controlled clinical trial. Biometrics. 1975;31(1):103-115.
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.
Rozen TD, Fishman RS. Cluster headache in the United States of America: demographics, 
clinical characteristics, triggers, suicidality, and personal burden. Headache. 2012;52(1):99-
113.
Tepper SJ, Stillman MJ. Cluster headache: potential options for medically refractory patients 
(when all else fails). Headache. 2013;53(7):1183-1190.
The Sumatriptan Cluster Headache Study Group. Treatment of Acute Cluster Headache with 
Sumatriptan. N Engl J Med. 1991;325:322-326.
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.
van Vliet JA, Eekers PJ, Haan J, Ferrari M. Features involved in the diagnostic delay of cluster 
headache. J Neurol Neurosurg Psychiatry. 2003;74(8):1123-1125.


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Attachment 1.Protocol CGAL Study Schedule


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Study Schedule, Protocol I5Q-MC-CGAL, SP I - SP III
Patient Status
Entering in active 
cluster period
Entering in Remission
Study Phase (SP)
SP I/II
SP I
SP II
SP III
Comments
Description
Screening/ Pre-
Rand. Diary
Screening
Pre-Rand. 
Diary 
Treatment
Visit
1
(Note:  V1 and V2 
procedures are 
combined into V1)
1
2
3
4 (Ph.
visit)
5
6 (Ph.
visit)
7
Phone visits (V4 and V6) are
contacts between office visits to 
collect any spontaneously 
reported AE
Min range:  
SP I/II–10 to 15d
Allowable 
range b/w 
V1 and V2:  
0 d to 1 yr
Min range:  
SPII–10 to 
15d; 
V2 to V3–5d
For flow of patients through SP I 
and SP II, please refer to the study 
design Section 7.1.
Visit Day
Day 1
Day 7
Day 30
Day 37
Day 60
Month
1
2
Interval (days) since 
previous office visit
7
30
7
30
The interval from V3 to V5 and 
the interval from V5 to V7 should 
be no less than 28 days.
Interval allowance 
(days) 
+/-1
+5/-2
+/-1
+5/-2
Informed consent 
X
X
Patients who have an extended 
period between V1 and V2 may 
need to be re-consented according 
to local regulations. 
Sites will be encouraged to stay in 
contact with patients during SP I 
who enter in remission.
Inclusion and 
exclusion criteria
X
X
X
X
Dispense ePRO 
diary 
X
X
Demographics 
X
X
Med history and pre-
existing conditions
X
X


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Study Schedule, Protocol I5Q-MC-CGAL, SP I - SP III
Patient Status
Entering in active 
cluster period
Entering in Remission
Study Phase (SP)
SP I/II
SP I
SP II
SP III
Comments
Description
Screening/ Pre-
Rand. Diary
Screening
Pre-Rand. 
Diary 
Treatment
Visit
1
(Note:  V1 and V2 
procedures are 
combined into V1)
1
2
3
4 (Ph.
visit)
5
6 (Ph.
visit)
7
Phone visits (V4 and V6) are
contacts between office visits to 
collect any spontaneously reported 
AE
Treatment
X
X
IP injections are to occur after all 
other visit procedures are 
completed.  Following the first 
dose at V3, patients will be 
observed for 30 min in the office
Prior cluster headache 
attack history
X
X
ECG
X
X
X
All ECGs should be collected prior 
to blood draws and dosing.  
Patients must be supine for approx.
5-10 min before ECG collection 
and remain supine but awake
during ECG collection
Physical 
examination
X
X
X
Must include a brief neurological 
exam
Caffeine use
X
X
Tobacco use 
(smoking and non-
smoking )
X
X
Nicotine use
X
X
Alcohol use
X
X
Height
X
X
X
Weight
X
X
X
X


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Study Schedule, Protocol I5Q-MC-CGAL, SP I - SP III
Patient Status
Entering in active 
cluster period
Entering in Remission
Study Phase (SP)
SP I/II
SP I
SP II
SP III
Comments
Description
Screening/ Pre-
Rand. Diary
Screening
Pre-Rand. 
Diary 
Treatment
Visit
1
(Note:  V1 and V2 
procedures are 
combined into V1)
1
2
3
4 (Ph.
visit)
5
6 (Ph.
visit)
7
Phone visits (V4 and V6) are
contacts between office visits to 
collect any spontaneously reported 
AE
Waist and Hip 
Circumference
X
X
Vital signs
X
X
X
X
X
X
Vital signs will be taken at
scheduled and unscheduled office 
visits and 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.  
Blood pressure will be assessed by 
utilizing a calibrated machine that 
will be provided to the sites.
Hematology
X
X
X
Clinical chemistrya
X
X
X*
X*
*Fasting chemistry labs (no food or 
drink, except water, for at least 8 
hrs) to be performed at this visit. 
Urinalysis
X
X
X
HbA1C
X
X
X
Serum Pregnancy or 
FSH 
X
X
Female patients
Urine drug screen
X
X
Randomization
X


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Study Schedule, Protocol I5Q-MC-CGAL, SP I - SP III
Patient Status
Entering in active 
cluster period
Entering in Remission
Study Phase (SP)
SP I/II
SP I
SP II
SP III
Comments
Description
Screening/ Pre-
Rand. Diary
Screening
Pre-Rand. 
Diary 
Treatment
Visit
1
(Note:  V1 and V2 
procedures are 
combined into V1)
1
2
3
4 (Ph.
visit)
5
6 (Ph.
visit)
7
Phone visits (V4 and V6) are
contacts between office visits to 
collect any spontaneously reported 
AE
Immunogenicity
X
X
X
Immunogenicity samples must be 
collected prior to dose 
administration if the visit is a 
dosing visit.  Samples will be taken 
in the event of early termination.  
The timing of samples will be 
recorded. 
Plasma Storage 
Sample (K+/EDTA)
X
X
X
X
X
X
Samples must be collected prior to 
dose administration if the visit is a
dosing visit.  The timing of the 
samples will be recorded.
These samples will be collected in 
an K+/EDTA container.
PK blood sampling
X
X
Samples must be collected prior to 
dose administration if the visit is a
dosing visit.  The timing of the 
samples will be recorded.
CCI


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Study Schedule, Protocol I5Q-MC-CGAL, SP I - SP III
Patient Status
Entering in active 
cluster period
Entering in Remission
Study Phase (SP)
SP I/II
SP I
SP II
SP III
Comments
Description
Screening/ Pre-
Rand. Diary
Screening
Pre-Rand. 
Diary 
Treatment
Visit
1
(Note:  V1 and V2 
procedures are 
combined into V1)
1
2
3
4 (Ph.
visit)
5
6 (Ph.
visit)
7
Phone visits (V4 and V6) are
contacts between office visits to 
collect any spontaneously reported 
AE
RNA storage sample
X
X
X
X
X
Sample must be collected in a 
Tempus tube
PGI-I
X
X
C-SSRS/SHSF, 
SHFU
X
X
X
X
X
X
To be completed at scheduled and 
unscheduled office visits
Recording of AEs
X
X
X
X
X
X
X
X
Review Diary data
X
X
X
Following Informed Consent, 
patients are required to complete 
their diaries daily beginning on the 
day of their next cluster headache 
attack.  Sites should review the 
diary compliance with the patient 
during office visits.
Concomitant 
medications
X
X
X
X
X
X
Abbreviations:  AE = adverse event; approx. = approximately; b/w = between; CGRP = calcitonin-gene related peptide; C-SSRS = Columbia-Suicide Severity 
Rating Scale; d = day; ECG = electrocardiogram; ePRO = electronic patient-reported outcome; ET = early termination; FSH = follicle stimulating hormone; 
hrs = hours; IP = investigational product; min = minute; PGI-I = Patient Global Impression of Improvement; Ph = phone; Pre-Rand. = pre-randomization; PK 
= pharmacokinetics; SHSF = Self-Harm Supplement Form; SHFU = Self-Harm Follow-Up Form; SP = Study Phase; V = visit; yr = year.
a
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may be required in follow-up with patients in consultation with 
the Lilly, or its designee, clinical research physician.  See Attachment 3 for more details regarding specific hepatic monitoring tests.  If the patient has 
discontinued the trial and returns for hepatic follow-up, the site should use the 800 series as the visit designation.
CCI


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Study Schedule, I5Q-MC-CGAL, SP IV-ET
Study Phase (SP)
SP IV
ET
Comments
Description
Post-treatment
Interval (days) since 
previous office visit
60
60
Interval allowance (days) 
+/- 8
+/- 8
Visit
8
9
Visit Day
Day 120
Day 180
ET
Month
4
6
ECG
X
X
All ECGs should be collected prior to blood draws and 
dosing.  Patients must be supine for approx. 5-10 min
before ECG collection and remain supine but awake 
during ECG collection
Weight
X
X
Vital signs
X
X
X
Vital signs will be taken at scheduled and unscheduled
office visits and 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. Blood pressure will 
be assessed by utilizing a calibrated machine that will 
be provided to the sites.
Hematology
X
X
Clinical chemistrya
X*
X*
*Fasting chemistry labs (no food or drink, except 
water, for at least 8 hrs) to be performed at this visit.
Urinalysis
X
X
HbA1C
X
X
Serum Pregnancy
X
X
Females only
Immunogenicity
X
X
Immunogenicity samples must be collected prior to 
dose administration if the visit is a dosing visit.  
Samples will be taken in the event of early termination.  
The timing of samples will be recorded. 
Plasma Storage Sample
(K+/EDTA)
X
X
Samples must be collected prior to dose administration 
if the visit is a dosing visit.  The timing of the samples 
will be recorded.
These samples will be collected in an K+/EDTA 
container.
PK blood sampling
X
X
X
Samples must be collected prior to dose administration 
if the visit is a dosing visit.  The timing of the samples 
will be recorded.
RNA storage sample
X
X
Sample must be collected in a Tempus tube
CCI


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Study Schedule, I5Q-MC-CGAL, SP IV-ET 
Study Phase (SP)
SP IV
ET
Comments
Description
Post-treatment
Interval (days) since 
previous office visit
60
60
Interval allowance (days) 
+/- 8
+/- 8
Visit
8
9
PGI-I
X
X
C-SSRS/SHSF, SHFU
X
X
X
To be completed at scheduled and unscheduled office 
visits
Recording of AEs
X
X
X
Concomitant 
medications
X
X
X
Abbreviations:  AE = adverse event; approx. = approximately; b/w = between; CGRP = calcitonin-gene related 
peptide; C-SSRS = Columbia-Suicide Severity Rating Scale; d = day; ECG = electrocardiogram; ePRO = 
electronic patient-reported outcome; ET = early termination; FSH = follicle stimulating hormone; hrs = hours; IP 
= investigational product; min = minute; PGI-I = Patient Global Impression of Improvement; Ph = phone; Pre-
Rand. = pre-randomization; PK = pharmacokinetics; SHSF = Self-Harm Supplement Form; SHFU = Self-Harm 
Follow-Up Form; SP = Study Phase; V = visit; yr = year.
a
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may be required in 
follow-up with patients in consultation with the Lilly, or its designee, clinical research physician.  See 
Attachment 3 for more details regarding specific hepatic monitoring tests.  If the patient has discontinued the trial 
and returns for hepatic follow-up, the site should use the 800 series as the visit designation.


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Attachment 2.Protocol CGAL Clinical Laboratory Tests 


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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
Calcium
HbA1c
Glucose (fasting)a
Urinalysis:
Albumin
Specific gravity
Creatine kinase (CK)
pH
Total cholesterola
Protein
Glucose
Ketones
Blood
Urine leukocyte esterase
HDLa
Other
 
PK Sample (LY2951742 serum concentration 
determination)
Immunogenicity
Urine Drug Screenb
Pregnancy Test (females only)
c
Serum pregnancy or FSH
Stored Samples
Plasma Storage (K+/EDTA
) 
RNA
Abbreviations:  FSH = follicle-stimulating hormone; HDL = high density lipoprotein; PK = pharmacokinetic; RBC 
= red blood cells; RNA = ribonucleic acid; WBC = white blood cells.
a
Fasting at Visit V3, V7, V9 or early termination.
b
Performed at screening and may be repeated during the study at the discretion of the investigator.
c
Performed at screening per inclusion criteria number 8 and at V9 or ET.
CCI
CCI
CCI


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Attachment 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
GGT
CPK
Alkaline phosphatase isoenzymesa
Anti-Actin antibodya
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.


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Attachment 4.Protocol CGAL Sampling Summary
This table summarizes the maximum number of samples venipunctures and volumes for all 
sampling and tests during the study.  Fewer samples may actually be taken, but this will not 
require a protocol amendment.
Protocol I5Q-MC-CGAL Sampling Summary
Purpose
Sample 
Type
Maximum Amount 
per Sample 
Maximum 
Number Samples
Maximum Total 
Amount
Screening testsa
Blood
3.5 mL
3 
10.5 mL
Standard laboratory testsa
Blood
3.5 mL
6
21 mL
PK sample (determination 
of LY2951742 serum 
concentration)
Blood
2.5 mL
4
10 mL
Plasma storage sample
(K+/EDTA)
Blood
5 mL
6
30 mL
Immunogenicity samples
Blood
10 mL
4
40 mL
RNA storage sample
Blood
3 mL
5
15 mL
Total 
Blood
196 mL
Hepatic monitoringc
Blood
3 - 30 mL
-
-
Abbreviation:  CGRP = calcitonin gene related peptide; PK = pharmacokinetic; RNA = ribonucleic acid.
a
Additional samples may be drawn if needed for safety purposes.
c
Based on laboratory safety values, unscheduled hepatic monitoring testing may be performed as part of patient 
follow-up, in consultation with Lilly Designated Medical Monitor.
CCI
CCI
CCI


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Attachment 5.Protocol Amendment Summary:  
I5Q-MC-CGAL(d)
Overview
Protocol I5Q-MC-CGAL (c), A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study 
of LY2951742 in Patients with Episodic Cluster Headache, has been amended. The new 
protocol is indicated by amendment (d) 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:

Updated the primary endpoint to be the overall treatment effect across Weeks 1 to 3 in 
weekly cluster headache attack frequency rather than the treatment effect at a single time 
point (Week 3) in that treatment period to enable evaluation of treatment effect over a 3-
week period.  

Clarified that baseline daily average cluster headache attack frequency categorical 
variable will be a covariate in the MMRM model for efficacy measures not derived from 
cluster headache attack frequency since it was considered possibly prognostic and was 
included in the dynamic randomization algorithim.  

Safety population and modal treatment description were added for safety analyses since 
it is more appropriate to present safety results by the actual treatments patients received.

Clarified the blinding of study personnel following database lock for the analysis of the 
double-blind treatment phase.  

Clarified the baseline patient characteristics in Section 12.2.3.

The ePRO diary primary efficacy compliance and overall ePRO diary compliance are 
combined into one diary compliance calculation since no partially completed diary can 
be submitted.

The parameter of large clinical trial population-based QT correction (QTcLCTPB) was 
removed for electrocardiogram (ECG) analysis per updated guidance from an internal 
subject matter expert group.  The analysis of QTc and QTcF remain.

Updated the protocol to reflect that the interim analysis for sample size re-estimation will 
not occur.

Minor editorial changes throughout the protocol as found.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore
Header
I5Q-MC-CGAL(cd) Clinical Protocol
Title
Protocol I5Q-MC-CGAL(cd)
2.
Synopsis
Study Rationale
LY2951742 (also known as galcanezumab) is a humanized monoclonal antibody that selectively 
binds to and neutralizes calcitonin-gene-related-peptide (CGRP) and has been identified for 
clinical development in pain conditions relevant to the CGRP pathway such as migraine and 
cluster headache.  
Primary Objective:  The primary objective of this study is to assess the efficacy of LY2951742 
300 mg every 30 days compared with placebo in reducing the frequency of weekly cluster 
headache attacks in patients with episodic cluster headache.  The primary outcome measure will 
be the weekly cluster headache attack frequency.  The primary endpoint will be the overall mean 
change from baseline in weekly cluster headache attack frequency from baseline toacross Weeks 
1 to Week 3 with LY2951742 compared with placebo.  Baseline is defined as the last 7 days in 
the eligibility report (pre-randomization diary phase).
Other Secondary Objectives:

To assess the development and consequences of anti-drug antibodies (ADA) to 
LY2951742 in patients exposed to LY2951742; to provide samples for subsequent 
evaluation of neutralizing ADAs (NAbBs) upon availability of the validated assay.
Exploratory Objectives:

Change in percentage of times using oxygen or triptan from baseline for each 
weekly interval through Week 8 comparing LY2951742 with placebo.

Change in percentage of times using triptan from baseline for each weekly 
interval through Week 8 comparing LY2951742 with placebo.


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Statistical Methods:
Unless otherwise specified, efficacy analyses during SP III will be conducted on an intent-to-
treat (ITT) population, which includes all patients who are randomized and receive at least one 1
dose of IP.  Patients in the ITT population will be analyzed according to the treatment group to 
which they were randomized.  The ITT population will be the primary population on which 
statistical analysis will be performed.  Safety analyses during SP III will be conducted on the 
safety population, which also includes all patients who were randomized and receive at least 1 
dose of study drug.  However, patients will be analyzed by actual study treatment received most 
often (modal treatment) during the double-blind treatment phase.  When change from baseline is 
assessed, the patient will be included in the analysis only if he/she has a baseline and a post-
baseline measurement.
For some of the analyses of the post-treatment phase, the post-treatment population will be used.  
Post-treatment population will be defined as all patients who entered the post-treatment phase 
(SP IV) as indicated by entering the firstany post-treatment visit.  Patients in the post-treatment 
population will be analyzed according to the treatment that they were randomized to at their 
randomization visit for analyses by treatment.  Details related to handling of missing data will be 
described in the SAP.
Treatment effects will be evaluated based on a 2-sided significance level of 0.05 for all the 
efficacy and safety analyses unless otherwise stated.  The 95% confidence intervals (CIs) for the 
difference in least-square means (LSMeans) between treatment`groups will be presented.  
Adjustments for multiple comparisons for the analyses corresponding to the primary and gated 
secondary objectives are described in the sections on the primary and secondary efficacy 
analyses below.  There will be no adjustments for multiplicity for analyses of other data.
Unless otherwise specified, when an analysis of variance (ANOVA) model is used to analyze a 
continuous efficacy variable, the model will contain the main effects of treatment, gender and 
pooled investigative site.  Similar logic is applied to an analysis of covariance (ANCOVA) 
model, which in general, refers to the ANOVA model with baseline values added as a covariate.
Categorical comparisons between treatment groups will be performed using Cochran-Mantel-
Haenszel (CMH) controlling for pooled investigative site and Fisher’s exact tests, where 
appropriate.
Efficacy – Primary:    
The primary analysis will be conducted by a restricted maximum likelihood-based (REML-
based), mixed-effects repeated measures (MMRM) analysis using all the longitudinal 
observations from Week 1 to Week 3.  The analysis of the primary outcome will be the contrast 
main effect of treatment between LY2951742 300 mg and placebo at across Weeks 1 to 3 of the 
treatment phase from a repeated measures analysis on mean change from baseline in the weekly 
attack frequency.  This provides the average treatment effect over the 3-week period.  Baseline is 
defined as the last 7 days in the eligibility report (pre-randomization diary phase).
If the sample size is increased as a result of the interim analysis, the Cui, Hung, and Wang 
(CHW) procedure (Cui et al. 1999) will be applied to the primary endpoint to control the type I 
error at a one sided α=0.025 significance level.  The CHW method ensures strong control of type 


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1 error when the sample size is increased in a data dependent manner.
If the sample size is increased as a result of the interim analysis, an unadjusted point estimate for 
the primary efficacy analysis will be calculated and reported.  A median unbiased point estimate 
and a stage-wise adjusted confidence interval for the primary efficacy analysis will be calculated 
and reported based on the approach described in Brannath, Mehta, and Posch (2009) to assess 
sensitivity of the point estimate.
Efficacy – Gated Secondary:  
If the sample size is increased, the CHW test statistic will be calculated for the gated secondary 
outcome.  The analysis of the secondary gatekeeper objective will be performed if the placebo 
versus LY2951742 comparison is significant for the primary efficacy analysis at a one sided 
α=0.025 significance level using the methodology described in the SAP.  
Safety:  The safety analyses will be conducted for SP III and SP IV as well as SP III and SP IV 
combined.  For SP III and SP IV combined, only repeated measures analysis and time to event 
analysis will be conducted.
The safety and tolerability of treatment will be assessed by summarizing the following:
•
Adverse events
o
TEAEs

by PT

by SOC

by maximum severity

by outcome

considered to be related to IP by investigator
o
SAEs
o
AE leading to discontinuation
•
Suicidal ideation and behaviors assessed by solicited questioning using the C-
SSRS
•
Vital signs and weight
•
Electrocardiograms
•
Laboratory measurements
•
Anti-LY2951742drug antibody
Unless specified otherwise, the categorical safety analyses will include both schedule and 
unscheduled visits.  
Comparisons between treatment groups for all categorical safety measures will be made using 
Fisher’s exact test for SP III with the ITT safety population


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4.
Abbreviations and Definitions
CHW
Cui, Hung, and Wang procedure
NABsNAb
neutralizing anti-drug antibodies
5.
Introduction
LY2951742 (also known as galcanezumab) is a humanized monoclonal antibody that binds to 
and neutralizes CGRP.  
6.
Objectives
6.1.
Primary Objective
The primary objective is to assess the efficacy of LY2951742 300 mg every 30 days compared 
with placebo in reducing the frequency of weekly cluster headache attacks in patients with 
episodic cluster headache.  The primary outcome measure will be the weekly cluster headache 
attack frequency.  The primary endpoint will be the overall mean change from baseline in weekly 
cluster headache attack frequency from baselineacross Weeks 1 to Week 3 with LY2951742
compared with placebo.  Baseline is defined as the last 7 days in the eligibility report (pre-
randomization diary phase).  
6.2.2. Other Secondary Objectives

To assess the development and consequences of anti-drug antibodies (ADA) to 
LY2951742 in patients exposed to LY2951742; to provide samples for subsequent 
evaluation of neutralizing ADAs (NABsNAb) upon availability of the validated assay.
6.3.
Exploratory Objectives
To assess whether galcanezumabLY2951742 is superior to placebo as measured by:

Change in percentage of times using oxygen or triptan from baseline for each 
weekly interval through Week 8 comparing LY2951742 with placebo.

Change in percentage of times using triptan from baseline for each weekly 
interval through Week 8 comparing LY2951742 with placebo.
7.2.
Discussion of Design and Control
The proposed duration of the double-blind treatment phase is 8 weeks, with the primary endpoint 
assessed acrossduring Weeks 1 to 3 after the first IP dose.  


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9.7.
Blinding
This is a double-blind study.  To preserve the blinding of the study, only a minimum number of 
Lilly personnel will see the randomization table and treatment assignments before the study is 
complete.
After the reporting database is locked for statistical analysis of the double-blind treatment phase, 
a limited number of sponsor personnel will be unblinded to complete the study report and 
prepare for regulatory submission.  However, any sponsor personnel continuing with the 
management and oversight of the trial will remain blinded to patients’ previous treatment 
assignment.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Unless otherwise specified, efficacy analyses during SP III will be conducted on an intent-to-
treat (ITT) population, which includes all patients who are randomized and receive at least one 1
dose of IP.  Patients in the ITT population will be analyzed according to the treatment group to 
which they were randomized.  The ITT population will be the primary population on which 
statistical analysis will be performed.  Safety analyses during SP III will be conducted on the 
safety population, which also includes all patients who were randomized and receive at least 1 
dose of study drug.  However, patients will be analyzed by actual study treatment received most 
often (modal treatment) during the double-blind treatment phase.  When change from baseline is 
assessed, the patient will be included in the analysis only if he/she has a baseline and a post-
baseline measurement.
For some of the analyses of the post-treatment phase, the post-treatment population will be used.  
Post-treatment population will be defined as all patients who entered the post-treatment phase 
(SP IV) as indicated by entering the firstany post-treatment visit.  Patients in the post-treatment 
population will be analyzed according to the treatment that they were randomized to at their 
randomization visit for analyses by treatment.
Details related to handling of missing data will be described in the SAP.
Treatment effects will be evaluated based on a 2-sided significance level of 0.05 for all the 
efficacy and safety analyses unless otherwise stated.  The 95% confidence intervals (CIs) for the 
difference in least-square means (LSMeans) between treatment`groups will be presented.  
Adjustments for multiple comparisons for the analyses corresponding to the primary and gated 
secondary objectives are described in the sections on the primary and secondary efficacy 
analyses below.  There will be no adjustments for multiplicity for analyses of other data.
Unless otherwise specified, when an analysis of variance (ANOVA) model is used to analyze a 
continuous efficacy variable, the model will contain the main effects of treatment, gender and 
pooled investigative site.  Similar logic is applied to an analysis of covariance (ANCOVA) 
model, which in general, refers to the ANOVA model with baseline values added as a covariate.


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Categorical comparisons between treatment groups will be performed using Cochran-Mantel-
Haenszel (CMH) controlling for pooled investigative site and Fisher’s exact tests, where 
appropriate.
12.2.3. Patient Characteristics
The following patient characteristics will be recorded at baseline and will be summarized by 
treatment groups for all ITT patients:
•
Demographic (age, gender, race, ethnicity, country, region, height, weight, BMI)
•
Baseline disease characteristics, such as:
o
Number of weekly cluster headache attacks
o
Number of times an abortive medication was taken
o
Mean Average severity of cluster headache pain
o
Mean Average cluster headache attack minutesduration
o
Number of times an abortive medication was taken per cluster headache
o
Number of times of using the oxygen or triptan
o
Number of times of using acetaminophen/paracetamol or NSAIDs
o
Percentage of times of using oxygen or triptan
o
Percentage of times of using acetaminophen/paracetamol or NSAIDs
12.2.5. Treatment Compliance
Treatment compliance will be calculated for SP III as:
number of full doses received * 100
number of intended full doses
Comparisons between treatments for treatment compliance will be performed using an ANOVA 
with treatment and pooled investigative site in the model.
12.2.6. ePRO Diary Compliance
The ePRO diary compliance at each weekly interval (including baseline, Week 1, 2, 3, 4, 5, 6, 7
and 8) will be calculated.  Diary compliance at each interval is calculated as:
Actual number of diary entry days in the interval ∗100
Expected number of diary entry days in the interval
Two ePRO diary compliance rate will be calculated:


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ePRO diary primary efficacy compliance
overall ePRO diary compliance
For ePRO diary primary efficacy compliance, the actual number of The diary entry days is 
calculated ascan only be saved and submitted afer all the required ePRO questions are answered, 
so the actual number of diary entry days represents the total number of days with non-missing 
answer to all the required cluster headache attack ePRO questions.  For overall ePRO diary 
compliance, the actual number of diary entry days will be calculated as the total number of days 
with a non-missing answer to all the cluster headache attack ePRO questions.
For both ePRO diary primary efficacy compliance and overall ePRO diary compliance, the The 
expected number of diary entry days will be calculated as (the last calendar date - the first 
calendar date in each interval +1).
Comparisons between diary compliance for each interval separately will be performed using an 
ANOVA with treatment and pooled investigative site in the model.
Compliance will also be listed by visit weekly interval for each patient.
12.2.7. Primary and Gated Outcome and Methodology
12.2.7.1. Primary Outcome
The primary analysis will be conducted by a restricted maximum likelihood-based (REML-
based), mixed-effects repeated measures (MMRM) analysis using all the longitudinal 
observations from Week 1 to Week 3.  The analysis of the primary outcome will be the contrast 
main effect of treatment between LY2951742 300 mg and placebo at across Weeks 1 to 3 of the 
treatment phase from a repeated measures analysis on mean change from baseline in the weekly 
attack frequency.  This provides the average treatment effect over the 3-week period.  Baseline is 
defined as the last 7 days in the eligibility report (pre-randomization diary phase).
If the sample size is increased as a result of the interim analysis, the Cui, Hung, and Wang 
(CHW) procedure (Cui et al. 1999) will be applied to the primary endpoint to control the type I 
error at a one sided α=0.025 significance level.  The CHW method ensures strong control of type 
1 error when the sample size is increased in a data dependent manner.
If the sample size is increased as a result of the interim analysis, an unadjusted point estimate for 
the primary efficacy analysis will be calculated and reported.  A median unbiased point estimate 
and a stage-wise adjusted confidence interval for the primary efficacy analysis will be calculated 
and reported based on the approach described in Brannath, Mehta, and Posch (2009) to assess 
sensitivity of the point estimate.
12.2.7.2. Gated Secondary
If the sample size is increased, the CHW test statistic will be calculated for the gated secondary 
outcome.  The analysis of the secondary gatekeeper objective will be performed if the placebo 
versus LY2951742 comparison is significant for the primary efficacy analysis at a one sided 
α=0.025 significance level using the methodology described in the SAP.  


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12.2.8. Other Efficacy Analyses
For the continuous secondary and exploratory efficacy measures, the change from baseline to 
each weekly interval post-baseline measure will be analyzed from repeated measures analyses.
For efficacy measures that are not derived from cluster headache attack frequency, the baseline 
average daily cluster headache attack frequency category (≤4 vs >4) will be added as a covariate 
in the MMRM model. 
In addition to the repeated measures analyses, for some of the secondary efficacy measures, the 
mean change from baseline to last observation carried forward (LOCF) endpoint for each 
treatment will be estimated for the continuous efficacy measures using ANCOVA models.
12.2.10
Safety Analyses
The safety analyses will be conducted for SP III and SP IV as well as SP III and SP IV 
combined.  For SP III and SP IV combined, only repeated measures analysis and time to event 
analysis will be conducted.
The safety and tolerability of treatment will be assessed by summarizing the following:
•
Adverse events
o
TEAEs

by PT

by SOC

by maximum severity

by outcome

considered to be related to IP by investigator
o
SAEs
o
AE leading to discontinuation
•
Suicidal ideation and behaviors assessed by solicited questioning using the C-
SSRS
•
Vital signs and weight
•
Electrocardiograms
•
Laboratory measurements
•
Anti-LY2951742drug antibody
12.2.10.1.
Categorical Safety Variables
Comparisons between treatment groups for all categorical safety measures will be made using 
Fisher’s exact test for SP III with the ITT safety population.  Descriptive statistics only will be 
presented for the treatment groups in SP IV with the post-treatment population.


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12.2.10.4.
Vital Signs and Weight
The incidence rates of patients with treatment-emergent vital sign and weight changes based at 
any time post-baseline and at LOCF endpoint will be assessed using Fisher’s exact tests.  
Specific criteria for treatment emergent definition will be documented in the SAP.
12.2.10.5.
Electrocardiogram Intervals and Heart Rate
Analyses of corrected QT (QTc) interval will be calculated using two correction formulas. 
Theand QTcF (measured in milliseconds [msec]) will be calculated with Fridericia’s formula as 
QT/RR⅓.  The Large Clinical Trial Population Based QT Correction (QTcLCTPB) (msec) will 
be calculated with the formula as QT/RR0.413.  The number and percent of patients meeting 
criteria for treatment-emergent abnormalities in ECG intervals (pulse rate [PR], QRS, and QTcF, 
and QTcLCTPB) and heart rate at any time during study will be summarized.  Treatment group 
comparisons will be performed using Fisher’s exact test.
12.2.10.6.
Laboratory Tests
The incidence rates of patients with treatment-emergent abnormal, high, or low laboratory values 
at any time post-baseline and at LOCF endpoint will be assessed using Fisher’s exact tests for 
each laboratory test.
12.2.12
Interim Analyses
Up to two2 formal interim analyses are planned for this trial.  The first interim analysis will 
occur during SP III which may result in increasing the sample size or stopping the trial for 
futility.  Details will be documented in the Statistical Analysis Center SAP, the ERB supplement 
and the Data Monitoring Committee (DMC) Charter.  However, this interim analysis for sample 
size re-estimation will not happen due to enrollment infeasibility.  The DMC will still 
independently monitor patient safety during this trial.
The othersecond interim analysis will be conducted after all patients have completed SP III, and 
thus, will be the final analysis of the primary efficacy endpoint.  This interim analysis will be 
conducted using internal unblinded study team members who do not have direct interaction with 
sites.
In order to minimize the operational and statistical bias that results from performing an interim 
analysis, the first interim analysis for this study will be conducted under the auspices of an 
independent DMC.  The DMC will also independently monitor patient safety during this trial.
Only the DMC is authorized to evaluate unblinded interim efficacy and safety analyses (prior to 
the completion of the double-blind treatment phase).  Study sites will receive information about 
interim results ONLY if they need to know for the safety of their patients.
14.
References
Brannath W, Mehta CR, Posch M. Exact confidence bounds following adaptive group sequential 
tests. Biometrics. 2009;65(2):539-546.
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical trials. 
Biometrics. 1999;55(3):853-857.


Leo Document ID = fae6126b-0387-4e12-8507-dc69d70e4a66
Approver:
Approval Date & Time: 29-Mar-2018 21:38:08 GMT
Signature meaning: Approved
Approver:
Approval Date & Time: 29-Mar-2018 21:38:08 GMT
Signature meaning: Approved
PPD
PPD

SAP_000.pdf: 
I5Q-MC-CGAL Statistical Analysis Plan Version 5  
 
 
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of LY2951742 in Patients with 
Episodic Cluster Headache  
 
 
NCT02397473 
 
 
Approval Date: 05-Apr-2018 
 
 


I5Q-MC-CGAL Statistical Analysis Plan Version 5
Page 1
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1.
Statistical Analysis Plan for Protocol I5Q-MC-CGAL:
A Phase 3 Randomized, Double-Blind, Placebo-Controlled 
Study of LY2951742 in Patients with Episodic 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 CGAL is a Phase 3 multi-center, outpatient, randomized, double-blind, placebo-
controlled study of galcanezumab 300 mg in the prevention of episodic cluster headache.  
The study consists of 4 study phases (SP):  SP I (screening/washout), SP II (pre-
randomization diary), SP III (randomized, double-blind, placebo-controlled treatment), and 
SP IV (post-treatment follow-up).
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I5Q-MC-CGAL
Phase 3
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:
18 December 2014
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly:
11 February 2015
Statistical Analysis Plan Version 3 electronically signed and approved by Lilly:
13 September 2016
Statistical Analysis Plan Version 4 electronically signed and approved by Lilly :
January 31 2018
Statistical Analysis Plan Version 5 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 05-Apr-2018 GMT


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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan for Protocol I5Q-MC-CGAL: A Phase 3 
Randomized, Double-Blind, Placebo-Controlled Study of 
LY2951742 in Patients with Episodic Cluster Headache .....................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives...............................................................................................................10
4.1.
Primary Objective ........................................................................................................10
4.2.
Secondary Objectives...................................................................................................10
4.2.1.
Gated Objective ...................................................................................................10
4.2.2.
Other Secondary Objectives .................................................................................10
4.3.
Exploratory Objectives.................................................................................................11
5.
A Priori Statistical Methods ..............................................................................................12
5.1.
Study Design................................................................................................................12
5.2.
Determination of Sample Size ......................................................................................12
5.3.
Randomization and Treatment Assignment ..................................................................12
5.4.
Endpoints.....................................................................................................................12
5.4.1.
Efficacy Endpoint ................................................................................................12
5.4.1.1.
Cluster Headache Attack Primary Endpoint ....................................................12
5.4.1.2.
Derived Variables for Cluster Headache Attacks ............................................12
5.4.1.3.
Patient Global Impression of Improvement Endpoint......................................16
5.4.2.
Safety Endpoints..................................................................................................16
5.4.3.
Immunogenicity Endpoints ..................................................................................16
5.4.4.
Biomarker Endpoints ...........................................................................................17
5.4.5.
Pharmacokinetic Assessment ...............................................................................17
5.5.
Statistical Analyses ......................................................................................................17
5.5.1.
General Considerations ........................................................................................17
5.5.1.1.
Adjustments for Covariates.............................................................................18
5.5.1.2.
Handling of Dropouts or Missing Data ...........................................................19
5.5.1.3.
Multicenter Studies.........................................................................................19
5.5.1.4.
Multiple Comparisons/Multiplicity.................................................................20
5.5.1.5.
Analysis Populations ......................................................................................20
5.5.1.6.
Baseline and Postbaseline Definition ..............................................................20
5.5.2.
Patient Disposition...............................................................................................24
5.5.3.
Important Protocol Deviations..............................................................................24
5.5.4.
Patient Characteristics..........................................................................................24


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5.5.5.
Exposure to Investigational Product .....................................................................25
5.5.5.1.
Duration of Exposure......................................................................................25
5.5.5.2.
Treatment Compliance....................................................................................26
5.5.6.
Electronic Patient-Reported Outcome Diary Compliance .....................................26
5.5.7.
Concomitant Therapy...........................................................................................26
5.5.8.
Efficacy Analyses ................................................................................................27
5.5.8.1.
Primary Outcome and Methodology ...............................................................27
5.5.8.2.
Gated Secondary.............................................................................................28
5.5.8.3.
Additional Secondary and Exploratory Efficacy Analyses ..............................29
5.5.9.
Safety Analyses....................................................................................................31
5.5.9.1.
Categorical Safety Variables...........................................................................32
5.5.9.1.1.
Adverse Events.........................................................................................32
5.5.9.1.1.1.
Potential Hypersensitivity Events........................................................33
5.5.9.1.1.2.
Adverse Events Related to Injection Sites ...........................................34
5.5.9.1.1.3.
Upper Respiratory Tract Infections .....................................................34
5.5.9.1.2.
Suicide-Related Thoughts and Behaviors..................................................34
5.5.9.1.3.
Vital Signs and Weight .............................................................................37
5.5.9.1.4.
Electrocardiogram Intervals and Heart Rate..............................................39
5.5.9.1.5.
Laboratory Tests.......................................................................................41
5.5.9.1.6.
Immunogenicity........................................................................................42
5.5.9.1.6.1.
Definitions of Sample Anti-drug Antibody Status ...............................42
5.5.9.1.6.2.
Definitions of Patient Anti-drug Antibody Status ................................43
5.5.9.1.6.3.
Analyses to Be Performed...................................................................44
5.5.9.2.
Continuous Safety Measures...........................................................................45
5.5.10.
Subgroup Analyses ..............................................................................................45
5.5.11.
Sensitivity Analysis..............................................................................................47
5.6.
Interim Analyses ..........................................................................................................49
5.7.
Unblinding Plan ...........................................................................................................49
5.8.
Reports to Be Generated at Each Interim and Final Database Lock...............................49
5.8.1.1.
Reports to Be Generated at Interim Database Lock.........................................49
5.8.1.2.
Reports to Be Generated at Final Database Lock ............................................50
5.9.
Clinical Trial Registry Analyses...................................................................................50
6.
References ........................................................................................................................51
7.
Appendices .......................................................................................................................52
CCI


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Table of Contents
Table
Page
Table CGAL.5.1. Example of Missing Data Imputation Outcome..............................................14
Table CGAL.5.2. Patient Population with Baseline and Postbaseline Definitions by Study 
Phase and Type of Analysis ...........................................................................21
Table CGAL.5.3. Other Secondary and Exploratory Efficacy Variables and Their 
Derivation......................................................................................................30
Table CGAL.5.4. Criteria for Treatment-Emergent, Potentially Clinical Significant and 
Categorical Changes and Sustained Elevation in Vital Signs and Weight.......38
Table CGAL.5.5. Criteria for Treatment-Emergent Changes in ECG Intervals and Heart 
Rate...............................................................................................................40
Table CGAL.5.6.Sample ADA Assay Results...........................................................................43
Table CGAL.5.7.Sample Clinical ADA Interpretation Results..................................................43
Table CGAL.5.8. Definition of Subgroup Variables ..................................................................45
Table CGAL.5.9.Subgroup Analyses........................................................................................46


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Table of Contents
Appendix
Page
Appendix 1.
Description of Important Protocol Deviations ................................................53


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 was approved on 18 December 2014. 
Statistical Analysis Plan Version 2 was approved prior to first patient visit and any unblinding.  
The overall changes and rationale for the changes incorporated in Version 2 are as follows:

The electronic patient reported outcome (ePRO) diary will now collect the average 
duration and average pain for the time period rather than for each attack.  Thus the 
derivation for mean severity and mean duration of cluster headache attack were updated.

The approach for missing data was updated for each weekly interval.
o
1) If there are less than or equal to 3 days with nonmissing answer to cluster 
headache attack frequency in the weekly interval; or 2) the primary efficacy 
compliance rate is less than or equal to 50%, then the weekly interval will be 
considered missing; 
o
Otherwise, 1) if there are greater than or equal to 4 days with nonmissing answer 
to cluster headache attack frequency in the weekly interval; and 2) the primary 
efficacy compliance rate is greater than 50%, then the average number of cluster 
headache attacks across the nonmissing days will be used to impute the missing 
days.

The algorithm for pooling of sites was updated.

The primary endpoint point estimate was updated to use the unadjusted estimate, and the 
median unbiased estimate will be used for sensitivity.

ePRO diary compliance was updated to calculate both ePRO diary primary efficacy 
compliance rate and overall ePRO diary compliance rate.

Addition of analysis for change from baseline in total weekly dose of sumatriptan Sc, 
sumatriptan nasal spray, and zolmitriptan nasal spray separately as well as combined.
Statistical Analysis Plan Version 3 was approved prior to IA1.  The changes incorporated in 
Version 3 are as follows:

Posttreatment follow-up phase safety analyses will have only 1 baseline.

A section on protocol violations to be identified was added.

Sensitivity analyses were updated, to be consistent with other Phase 3 studies of 
LY2951742.

Infections section will only deal with upper respiratory tract infections; analyses were 
modified to be consistent with other Phase 3 studies of LY2951742.

For Columbia-Suicide Severity Rating Scale (C-SSRS), 1 bullet was split into 2 to 
enhance readability, and baseline definition for improvement from baseline analysis was 
clarified.


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
Criteria for sustained elevation in diastolic blood pressure was changed to be consistent 
with the single time point analysis.

An additional criteria threshold for QTc increase was added.

Analyses of elevations in hepatic laboratory tests were clarified, and an additional subset 
was added.

Immunogenicity analyses were updated to be consistent with other Phase 3 studies of 
LY2951742.

An additional subgroup analysis category, for age, was added.

Some minor corrections and clarifications were made.
Statistical Analysis Plan Version 4 was approved after the last patient was randomized and prior 
to interim analysis (the first and final assessment of primary efficacy endpoint after all patients 
completed double-blind phase, which is the first unblinding to study team).  Enrollment in the 
trial was terminated (due to enrollment infeasibility) prior to reaching the sample size target for 
the originally planned interim analysis.  Therefore, the  planned interim analysis for sample size 
re-estimation did not occur. 
In the SAP Version 4, the updates were made mainly for incorporating the recent learnings from 
migraine data or for consistency across the galcanezumab program.  The changes incorporated in 
Version 4 of the SAP are summarized as follows:

LY2951742 was replaced by galcanezumab in the body of the SAP.

Consistent with the primary endpoint and analysis methodology for the pivotal migraine 
studies, the primary endpoint was updated to be the overall treatment effect over the 
Weeks 1 to 3 during the double-blind treatment phase, rather than the treatment effect at 
the single time point, Week 3. 

In Section 5.4.1.2, the exploratory endpoints for severity and duration of cluster headache 
attack pain and for the abortive medications were updated to clarify the research 
questions and the derivations were modified correspondingly. 

In Section 5.5.1.1 and 5.5.8.3, it was clarified that, for other secondary and exploratory 
efficacy measures that are not derived from cluster headache frequency, the baseline 
average daily cluster headache attack frequency category variable is included in the 
statistical analysis models. 

The list of analyses for other secondary and exploratory efficacy variables were updated 
in Table CGAL.5.3.  Last observation carried forward (LOCF) analysis for some 
exploratory variables was removed.

Since no partially completed diary can be submitted, the ePRO diary primary efficacy 
compliance and overall ePRO diary compliance are combined into 1 diary compliance 
calculation in Section 5.5.6.


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
In Section 5.5.1 and Table CGAL.5.2, safety population and modal treatment description 
for SP III were added for safety analyses since it is more appropriate to present safety 
results by the actual treatments patients received.

Terminologies and identification criteria were updated for adverse event of special 
interest (AESIs) for the consistency across the galcanezumab program.

In Section 5.5.9.1.3, detailed baseline and postbaseline definition for vital signs and 
weight were added.  The patient populations for analysis that do not satisfy treatment-
emergent definition were removed from Table CGAL.5.4.  

In Section 5.5.9.1.4, the parameter of large clinical trial population based QT correction 
(QTcLCTPB) was removed for electrocardiogram (ECG) analysis.  The detailed baseline 
and postbaseline definitions for ECG were added.

In Section 5.5.9.2, for continuous safety measures, Box-whisker plots with summary 
tables for SP III replaced LOCF and repeated measures analysis.

Section 5.5.9.1.6 of Immunogenicity was updated to clarify definitions and modify 
analyses to focus on evaluation of the incidence of baseline anti-drug antibodies (ADA)
and treatment-emergent ADA.

Subgroup analysis for safety endpoints were removed due to the small size of the study.  
A few subgroup variables for the efficacy endpoint were removed due to the small size in 
subgroups.

Section 5.6, Interim Analysis is updated to explain the changes in the interim analysis 
plan.

Since the originally planned interim analysis for sample size re-estimation will not be 
conducted due to enrollment infeasibility, all languages and methodology descriptions 
related to sample size increase are removed.

In Section 5.8, reports to be generated were updated to reflect that analyses from all SPs
specified in this SAP will be performed at the interim analysis instead of only performing 
analyses for SP III.  However, the analyses conducted for SP III will be deemed final 
since all patients will complete SP III at the interim analysis.  The analyses using data 
from SP IV will be rerun and updated when the completed data are available at the final 
database lock.

An appendix of important protocol deviations was added.

Other minor corrections, modifications, and clarifications were made.
Statistical Analysis Plan Version 5 has been approved prior to the interim analysis (the first and 
final assessment of primary efficacy endpoint after all patients completed double-blind phase, 
which is the first unblinding to study team).  There is no modification to the primary analysis 
methodologies for the primary, key secondary, and other secondary efficacy endpoints.  The 
changes incorporated in Version 5 are summarized as follows:


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
In Section 5.4.1.2, the exploratory endpoint for cluster headache attack duration was 
modified from “average weekly cluster headache attack minutes per attack for the 
remaining cluster headache days” to “weekly total cluster headache attack duration.” An 
exploratory responder endpoint for the weekly total cluster headache attack duration that 
is defined as 30% or greater reduction is also added.

In Section 5.5.9.1.2, removed the requirement of needing at least 4 events occurred in at 
least one treatment to display p-value.

In Table CGAL.5.4, added additional patient populations for analysis of treatment-
emergent, potentially clinically significant changes and sustained elevation in vital signs.  

In Section 5.5.10, additional subgroup variables were added for subgroup analysis.

In the table of Description of Important Protocol Deviations in Appendix 1, updated the 
data source of the Important Protocol Deviations (IPDs) to only display the final data 
source for the IPD analysis. Two new IPDs were added.  
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4.
Study Objectives
4.1.
Primary Objective
The primary objective is to assess the efficacy of galcanezumab 300 mg every 30 days compared 
with placebo in reducing the frequency of weekly cluster headache attacks in patients with 
episodic cluster headache.  The primary outcome measure will be the weekly cluster headache 
attack frequency.  The primary endpoint will be the overall mean change from baseline in weekly 
cluster headache attack frequency across Weeks 1 to 3 with galcanezumab compared with 
placebo.  Baseline is defined as the last 7 days in the eligibility report (prerandomization diary 
phase).
4.2.
Secondary Objectives
4.2.1. Gated Objective
To assess the efficacy of galcanezumab compared with placebo in the proportion of patients 
meeting response at Week 3.  For this analysis, response is defined as a reduction from baseline 
of 50% or greater in the weekly cluster headache attack frequency.
4.2.2. Other Secondary Objectives

To assess whether galcanezumab is superior to placebo on the following:
o
The proportion of patients with a 50% or greater reduction in the weekly 
number of cluster headache attacks from baseline for each weekly interval 
through Week 8
o
The proportion of patients with a 30% or greater reduction in the weekly 
number of cluster headache attacks from baseline for each weekly interval 
through Week 8
o
Mean change in the weekly cluster headache attack frequency from baseline 
for each weekly interval through Week 8
o
Proportion of patients reporting a score of 1 (“very much better”) or 2 (“much 
better”) on the Patient Global Impression of Improvement (PGI-I) at Week 4 
and Week 8.

To compare the safety and tolerability of galcanezumab with placebo in patients with 
episodic cluster headache using the following measures:
o
spontaneously reported treatment-emergent adverse events (TEAEs)
o
serious adverse events (SAEs)
o
discontinuation rates
o
suicidal ideation and behaviors assessed by solicited questioning using the C-
SSRS


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
To assess the development and consequences of ADA to galcanezumab in patients 
exposed to galcanezumab; to provide samples for subsequent evaluation of 
neutralizing ADA (NAb).

To evaluate the pharmacokinetics of galcanezumab.
4.3.
Exploratory Objectives
To assess whether galcanezumab is superior to placebo as measured by the following:

Mean change in the weekly number of times an abortive medication was taken from 
baseline for each weekly interval through Week 8 comparing galcanezumab with 
placebo.

Change in percentage of times using oxygen from baseline for each weekly interval 
through Week 8 comparing galcanezumab with placebo.

Change in percentage of times using triptan from baseline for each weekly interval 
through Week 8 comparing galcanezumab with placebo.

Change in percentage of times of using acetaminophen/paracetamol or nonsteroidal 
anti-inflammatory drugs (NSAIDs) from baseline for each weekly interval through 
Week 8 comparing galcanezumab with placebo.

The proportion of patients with a 75% or greater reduction in the weekly number of 
cluster headache attacks from baseline for each weekly interval through Week 8 
comparing galcanezumab with placebo. 

The proportion of patients with a 100% reduction in the weekly number of cluster 
headache attacks from baseline for each weekly interval through Week 8 comparing 
galcanezumab with placebo. 

Mean change from baseline in the cluster headache attack average weekly pain 
severity (based on 5-point scale) from baseline through Week 8 comparing 
galcanezumab with placebo.
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5.
A Priori Statistical Methods
5.1.
Study Design
Study CGAL is a Phase 3 multi-center, outpatient, randomized, double-blind, placebo-controlled 
study of LY2951742 300 mg  in the prevention of episodic cluster headache.  The study has 4
study phases (SP): SP I (screening/washout), SP II (pre-randomization diary), SP III
(randomized, double-blind, placebo-controlled treatment), and SP IV (post-treatment follow-up). 
Patients who discontinue the study during the double-blind treatment phase should enter the 
post-treatment follow-up phase.
5.2.
Determination of Sample Size
The study is planned to have a minimum of approximately 162 patients randomized 1:1 to 
placebo or galcanezumab 300 mg with the opportunity to increase the final sample size at an 
interim analysis if indicated in order to maintain a well-powered study. To preserve blinding, 
details of the sample size and power calculations are omitted from this SAP and are provided in a 
separate document to the Ethical Review Board (ERB).
5.3.
Randomization and Treatment Assignment
At Visit 3, eligible patients will be randomized in a 1:1 ratio to double-blind placebo or 
galcanezumab 300 mg (GMB300mg), respectively.  To achieve marginal balance of treatment 
assignments for the factors of gender, average daily attack frequency (≤4 attacks per day, >4 
attacks per day) and investigative site, randomization will be conducted with a dynamic 
allocation (minimization) method (Pocock and Simon 1975) with target probability of 0.8. 
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS). 
5.4.
Endpoints
5.4.1. Efficacy Endpoint
5.4.1.1.
Cluster Headache Attack Primary Endpoint
Patient-Rated Daily Electronic Patient-Reported Outcome (ePRO) Diary: Patients will be asked 
to record the number of cluster headache attacks in their daily ePRO diary during SP II and SP 
III, which is used to derive the primary efficacy endpoint. Information regarding abortive 
medication use, cluster headache attack duration on average, and cluster headache attack pain 
severity on average 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 (The 
Sumatriptan Cluster Headache Study Group 1991).  Patients should record all cluster attacks 
regardless of attack duration.
5.4.1.2.
Derived Variables for Cluster Headache Attacks
In Study CGAL, for primary measure of cluster headache attacks, the daily data for each patient 
(including last 7 days in the eligibility report [prerandomization diary phase], 8 weeks of daily 


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data during treatment) will be converted into 9 roughly 7-calendar day intervals: the baseline 7-
day interval, Week 1, 2, 3, 4, 5, 6, 7, and 8.  Each day, the patient may report zero, 1, or multiple 
cluster headache attacks.  Any ePRO diary data reported beyond the protocol defined collection 
period will not be used for statistical analysis.
The approach to split the postbaseline data into weekly intervals is done as follows:

Firstly, postbaseline daily data will be split into Weeks 1 to 4 versus Weeks 5 to 8 using 
1st and 2nd injection date. All data ≥1st injection date and <2nd injection date will be 
considered as Weeks 1 to 4; all data ≥2nd injection date and < treatment phase 
disposition date will be considered as Weeks 5 to 8. If 2nd injection date is missing, then 
all the data before treatment phase disposition date will be put into Weeks 1 to 4.

Secondly, data within Weeks 1, 2, and 3 will be determined using calendar days. In other 
words, the 1st injection date will be considered as Day 1, then Days 1 to 7 will be 
Week 1; Days 8 to 14 will be Week 2; Days 15 to 21 will be Week 3. Week 4 will 
include all the data from Day 22 to the date before the 2nd injection (or before the 
treatment phase disposition date if second injection date is missing).

Thirdly, if the 2nd injection date is not missing, the data within Weeks 5, 6, 7, and 8 will 
be determined using calendar days. In other words, the 2nd injection date will be 
considered as Day 1, then Days 1 to 7 will be Week 5; Days 8 to 14 will be Week 6; 
Days 15 to 21 will be Week 7. Week 8 will include all the data from Day 22 to the date 
before the treatment phase disposition date.
For each weekly interval, the following missing data imputation method will be used:

1) if there are less than or equal to 3 days with nonmissing answer to cluster headache 
attack frequency in the weekly interval; or 2) the diary compliance rate is less than or 
equal to 50%, then the weekly interval will be considered missing; 

Otherwise, 1) if there are greater than or equal to 4 days with nonmissing answer to 
cluster headache attack frequency in the weekly interval; and 2) the diary compliance 
rate is greater than 50%, then the average number of cluster headache attacks across the 
nonmissing days will be used to impute the missing days.  Furthermore, the total cluster 
headache attack frequency during the weekly interval will be calculated as the average 
number of cluster headache attacks across nonmissing days times the actual number of 
calendar days within each weekly interval.
The same missing data imputation approach will also be applied to secondary and exploratory 
efficacy measures that are derived from ePRO data.
Then to estimate a weekly outcome of the total frequency for an efficacy measure from ePRO 
diary, the data within each week will be adjusted to a 7-day interval by multiplying 
.
 , where “x” 
is the actual number of calendar days within each weekly interval.  Lastly, the change from 
baseline to Weeks 1, 2, 3, 4, 5, 6, 7, and 8 will be derived.
An example of missing data imputation is described below in Table CGAL.5.1.


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Table CGAL.5.1.
Example of Missing Data Imputation Outcome
Example 1
Example 2
Number of 
Calendar 
Days
Number of Days 
with Nonmissing 
Answer to Cluster 
Headache Attack 
Frequency
Missing 
Data 
Imputation
Number of 
Calendar 
Days
Number of Days 
with Nonmissing 
Answer to Cluster 
Headache Attack 
Frequency
Missing 
Data 
Imputation
Week 1
7
7
*a
7
7
*a
Week 2
7
4
*b
7
4
*b
Week 3
7
3
*c and *d
7
3
*c and *d
Week 4
13
6
*c
13
8
*b
Week 5
7
7
*a
7
7
*a
Week 6
7
7
*a
7
7
*a
Week 7
7
7
*a
7
7
*a
Week 8
5
3
*d
3
3
*d
*a No imputation.
*b The average number of cluster headache attacks across the non-missing days will be used to impute the missing 
days.
*c Set to missing (diary compliance ≤50%).
*d Set to missing (number of days with nonmissing answer to cluster headache attack frequency ≤3).
Gated secondary, other secondary, and exploratory efficacy measures will be derived for each 
patient for each 7-day interval as follows:

A 30%, 50%, 75%, and 100% responder is defined as any patient who has a ≥30%, 
≥50%, ≥75%, and =100% reduction in the number of cluster headache attacks in a 7-
day interval relative to baseline interval.  For 30%, 50%, 75%, and 100% responder 
definition, percentage reduction from baseline will be calculated as follows:
100 × (−1)X(weekly of cluster headache attacks at week X −
weekly of cluster headache attacks at baseline Interval)
weekly # of cluster headache attacks at baseline interval

Change from baseline for the remaining cluster headache attack days:
o
Change from baseline in the cluster headache attack average weekly pain severity 
for the remaining cluster headache attack days will be derived at each weekly 
interval through Week 8.  For the calculation of mean severity of cluster headache
attacks, severity has 5 categories: 0=no pain, 1=mild pain, 2=moderate pain, 
3=severe pain, and 4=very severe pain.  The mean severity for the remaining 
cluster headache attack days for each interval will be calculated as follows: 
Sum of average cluster headache severity per day during the interval
# of days with cluster headache attack during the interval


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If there is zero cluster headache attack within the weekly interval, then the mean 
severity of cluster headache attack for that interval will be considered not applicable 
hence missing at the interval for analyses purpose.

Change from baseline in weekly total cluster headache attack duration will be calculated
for each weekly interval. Average duration of cluster headache attacks during a 24-hour 
period was asked in the ePRO diary. Patients were instructed to round up to the next 
duration selection with following choices: 15 minutes, 30 minutes, 1 hour, 2 hours, 3 
hours, >3 hours. If the duration is >3 hours, then 4 hours will be imputed for the 
calculation of the total cluster headache attack duration. The total cluster headache attack
duration for each interval will be calculated as the summation of the average duration of 
cluster headache attack multiplied by the number of cluster headache attacks in the day
during the interval.  If the total duration is more than 24 hours for a day, it will be set to 
24 hours.

The proportion of patients with a 30% or greater reduction from baseline in the weekly 
total cluster headache attack duration will be calculated for each weekly interval.

Change from baseline in weekly number of times of using oxygen as abortive medication
at each interval will be calculated.

Change from baseline in weekly number of times of using oral triptan, sumatriptan nasal 
spray or zolmitriptan nasal spray as abortive medication at each interval will be 
calculated.

Change from baseline in weekly number of times of using sumatriptan Sc as abortive 
medication at each interval will be calculated.

Change from baseline in weekly number of times of using acetaminophen/paracetamol or 
NSAIDs as abortive medication at each interval will be derived.  

Change from baseline in number of times using oxygen as abortive medication per cluster 
headache attack at each interval will be derived.  The endpoint at each interval will be 
calculated as follows:
Total number of times using of oxygen during the interval
# of cluster headache attack during the interval

Change from baseline in number of times using oral triptan, sumatriptan nasal spray, or 
zolmitriptan nasal spray as abortive medication per cluster headache attack at each 
interval will be derived.  The endpoint at each interval will be calculated as follows:
Total number of times using the specified types of triptan during the interval
# of cluster headache attack during the interval

Change from baseline in number of times using sumatriptan Sc as abortive 
medication per cluster headache attack at each interval will be derived.

Change from baseline in number of times using acetaminophen/paracetamol or 
NSAIDs as abortive medication per cluster headache attack at each interval will 
be derived.  The endpoint at each interval will be calculated as follows:


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Total number of times using of acetaminophen/paracetamol or NSAIDs during the interval
# of cluster headache attack during the interval

Change from baseline in total weekly dose for oral triptan, sumatriptan nasal spray, and 
zolmitriptan nasal spray combined will be derived.  Total weekly dose will be calculated 
as follows:
Sum of doses of oral triptan, sumatriptan nasal spray, and zolmitriptan nasal spray
during the interval ∗7
# of nonmissing diary days during the interval

Change from baseline in total weekly dose for sumatriptan Sc, oral triptan, sumatriptan 
nasal spray, and zolmitriptan nasal spray will be derived separately.  Total weekly dose, 
respectively, will be calculated as follows:
Sum of doses of sumatriptan Sc during the interval ∗7
# of nonmissing diary days during the interval
Sum of doses of oral triptan during the interval ∗7
# of nonmissing diary days during the interval
Sum of doses of sumatriptan nasal spray during the interval ∗7
# of nonmissing diary days during the interval
Sum of doses of zolmitriptan nasal sprayduring the interval ∗7
# of nonmissing diary days during the interval
5.4.1.3.
Patient Global Impression of Improvement Endpoint
The PGI-I requests patients to mark the box that best describes their cluster headache condition 
since they started taking this medicine.  The options in the displayed boxes are represented on a 
7-point scale, with 1=very much better and 7=very much worse (Guy 1976).
The patient-reported PGI-I information will be captured at office visits. If the PGI-I collection 
date is greater than 10 days from the visit date, the record will not be used for analysis.
5.4.2. Safety Endpoints
Safety endpoints consist of the incidences of TEAEs, SAEs, and discontinuations due to adverse 
events (AEs), vital signs (blood pressure, pulse, and body temperature), weight, suicidal ideation 
and behaviors assessed by solicited questioning using the C-SSRS, ECGs, and laboratory 
measures (chemistry, hematology, and urinalysis).
5.4.3. Immunogenicity Endpoints
Immunogenicity endpoints consist of the incidences of antibodies to LY2951742 (ADA).  An 
additional endpoint is the incidence of NAb present in those trial participants with ADA.


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5.4.5. Pharmacokinetic Assessment
Pharmacokinetic assessment will be summarized in the pharmacokinetic/pharmacodynamic 
(PK/PD) SAP.
5.5.
Statistical Analyses
The protocol for this study was approved on 18 December 2014.  Protocol amendment (a) for 
this study was approved on 12 February 2015. Protocol amendment (b) for this study was 
approved on 22 December 2015.  Protocol amendment (c) for this study was approved on
10 February 2017.  The SAP Version 4 supersedes the statistical plans described in the protocol
and previous versions of the SAP.  
5.5.1. General Considerations
General aspects of statistical analyses are described below.
Unless otherwise specified, efficacy analyses during SP III will be conducted on an intent-to-
treat (ITT) population, which include all patients who are randomized and receive at least 1
dose of study drug. Patients in the ITT population will be analyzed according to the treatment 
group that they were randomized to. Safety analyses during SP III will be conducted on the 
safety population, which also includes all patients who are randomized and receive at least 1 
dose of study drug.  However, patients will be analyzed by actual study treatment received most 
often (modal treatment) during the double-blind treatment phase.  Modal treatment will be the 
same as randomized treatment except in some cases of incorrect treatment administration.  When 
mean change from baseline is assessed, the patient will be included in the analysis only if he or 
she has a baseline and a postbaseline measurement.
Unless otherwise specified, for analyses of posttreatment phase, the posttreatment population
will be used.  Posttreatment population will be defined as all patients who entered the post-
treatment phase (SP IV) as indicated by entering any posttreatment visit.
Statistical analysis will be carried out for the 8-week treatment phase (SP III), the 16-week post
treatment phase (SP IV) as well as the 8-week treatment and 16-week post treatment phases
combined (SP III/IV) as listed in Table CGAL.5.2.
Safety analyses (Section 5.5.9) in SP III and SP IV and analyses for exposure will be conducted
based on the modal treatment group patients have received (placebo or GMB300 mg).  For 
determining modal treatment, if there are 2 modes, then the modal treatment group will be 
GMB300 mg.
Unless otherwise specified, for the analyses in SP IV alone, no statistical comparisons between 
any treatment groups will be conducted.
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Since cluster headache attack information collected through ePROs will only be collected for 
SP III, analyses of ePRO data will be conducted at SP III only.
Treatment effects will be evaluated based on a 2-sided significance level of 0.05 for all the other 
efficacy and safety analyses. The 95% confidence intervals for the difference in least-square 
means (LSMeans) between treatment groups will be presented. Adjustments for multiple 
comparisons for the analyses corresponding to the primary and gated secondary objectives are 
described in the sections on the primary and secondary efficacy analyses below. There will be 
no adjustments for multiplicity for analyses of other data.  
A repeated measures analysis refers to a restricted maximum likelihood (REML)-based, mixed-
effects repeated measures (MMRM) analysis using all the longitudinal observations at each 
postbaseline visit/week.
Categorical comparisons between treatment groups for safety measures will be performed using 
Fisher’s exact tests, where appropriate.
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 changes, will be described 
in the SAP and/or in the clinical study report (CSR). 
Additional exploratory analyses of the data will be conducted as deemed appropriate.
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly) or 
designee. SAS® software will be used to perform most or all statistical analyses.
5.5.1.1.
Adjustments for Covariates
The repeated measures models will include the fixed, categorical effects of treatment, gender,
pooled investigative site, visit/week, and treatment-by-visit/week interaction, as well as the 
continuous, fixed covariates of baseline value.  Rules for pooling of investigative sites are 
described in Section 5.5.1.3. Note, in repeated measures analysis, visit will be used for measures 
collected at visit interval, while week will be used for all the ePRO data.
When an ANOVA model is used to analyze a continuous efficacy variable, the model will 
contain the main effects of treatment, gender and pooled investigative site, and appropriate 
baseline value included as a covariate. 
The categorical, pseudo-likelihood-based repeated measures models for the visit wise/week wise
binary outcomes of response will include the fixed, categorical effects of treatment, gender, 
visit/week, and treatment-by-visit/week interaction, as well as the continuous, fixed covariate of 
baseline value.  Pooled investigative site was not included in the model in order to increase the 
likelihood of convergence.
With the exception of efficacy analyses on cluster headache attack frequency or categorical 
analysis of response rate (such as 50% response rate) derived from cluster headache attack
frequency where the continuous value of baseline weekly cluster headache frequency will be 
used as covariate, all other efficacy analyses will include baseline average daily cluster headache 


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attack frequency category (≤4 vs. >4) as a covariate in the MMRM, GLIMMIX, and ANOVA
model.
5.5.1.2.
Handling of Dropouts or Missing Data
Repeated measures analyses will be used as the statistical approach for handling missing data.  
The model parameters are simultaneously estimated using restricted likelihood estimation 
incorporating all of the observed data.  Estimates have been shown to be unbiased when the 
missing data are missing at random and when there is ignorable non-random missing data
(Mallinckrodt 2008).  Missing at random (MAR) assumption will be evaluated using sensitivity 
analyses as defined in Section 5.5.11.
Approaches for Handling Missing Data for Derivation of Cluster Headache Attacks 
Derived from ePRO per 7-Day Interval
In Study CGAL, to derive the number of cluster headache attacks per 7-day interval, the daily 
data for each patient (including the last 7 days in the eligibility report [pre-randomization diary 
phase] and the 8 weeks of daily data during treatment) will be converted into 9 roughly 7-
calendar day intervals:  the baseline 7-day period, Weeks 1, 2, 3, 4, 5, 6, 7, and 8.  Each day, the 
patient may have zero, 1, or multiple cluster headache attacks.  For each weekly interval, the 
following missing data imputation method will be used:

1) if there are less than or equal to 3 days with nonmissing answer to cluster headache 
attack frequency in the weekly interval; or 2) the diary compliance rate is less than or 
equal to 50%, then the weekly interval will be considered missing;

Otherwise, 1) if there are greater than or equal to 4 days with nonmissing answer to 
cluster headache attack frequency in the weekly interval; and 2) the diary compliance 
rate is greater than 50%, then the average number of cluster headache attacks across the 
non-missing days will be used to impute the missing days.
For detailed example about missing data imputation, please see Section 5.4.1.2.
Then the change from baseline to Weeks 1, 2, 3, 4, 5, 6, 7, and 8 will be derived.
The same approach will also be applied to secondary and exploratory efficacy measures that 
derived from ePRO data.
5.5.1.3.
Multicenter Studies
The following investigative site pooling method will be used:
All investigative sites with fewer than 2 randomized patients per each treatment group with non-
missing cluster headache attacks during baseline interval and at least 1 postbaseline value will be 
pooled together within each country and considered a single site for analyses.  If this results in a 
pooled site still having fewer than 2 randomized patients per each treatment group, the pooled 
site will also be pooled with the next smallest site in that country, determined to be the site with 
the smallest number of randomized patients, or if more than 1 site meets that criterion, the 
smallest site with the lowest investigator number.  If this results in a pooled site still having 


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fewer than 2 patients randomized to each treatment arm, these sites will be pooled together with 
the next smallest site in the geographic region. Two geographic regions are defined, including 
US and Canada combined, as well as Europe. If this still results in a site having fewer than 
2 patients randomized to each treatment, then these sites will be pooled together with the next 
smallest site in the whole study.  
All analyses will use pooled investigative sites. The actual investigative site numbers will be 
included in the listings. 
5.5.1.4.
Multiple Comparisons/Multiplicity
The primary efficacy analysis will be the overall treatment effect of GMB300 mg every 30 days
versus placebo over Weeks 1 to 3 using a MMRM analysis, which is equivalent to the average of 
the MMRM-estimated weekly treatment effect over the 3-week period for change in weekly 
cluster headache attack frequency from baseline. The Type I error rate will be controlled at a 1-
sided 0.025 level for the primary efficacy analysis. 
A fixed sequential gatekeeper method will be utilized for testing secondary hypotheses to be 
eligible for inclusion in the proposed label. Specific details of the testing of the secondary 
gatekeeper objectives are provided in Section 5.5.8.2.
5.5.1.5.
Analysis Populations
Three analysis populations, including the ITT population, the safety population, and the 
posttreatment population, are defined in Section 5.5.1.
5.5.1.6.
Baseline and Postbaseline Definition
Table CGAL.5.2 describes the rules for determining the patient population and baseline and 
postbaseline observations for each study phase and type of analysis.  When “last of Visit x-x” is 
used in the table, the last nonmissing observation obtained in the visit interval will be used.  


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Table CGAL.5.2.
Patient Population with Baseline and Postbaseline Definitions by Study Phase and Type of Analysis
Study Phase/Analysis
Patient Population
Baseline 
Observation
Postbaseline 
Observation(s)
Study Phase III
Continuous secondary efficacy analyses (Repeated  
measures)
Patients in ITT population with a baseline and at 
least 1 postbaseline observation
Visit 3
All Visits 4-7
TEAEs
Safety population
All Visits 1-3 before 
dosing
Visit 3 after dosing through 
Visit 7 
SAEs, Discontinuations due to AEs
Safety population
NA
Visit 3 after dosing through 
Visit 7 
C-SSRS categorical analyses
Patients in safety population with a baseline and at 
least one postbaseline C-SSRS assessment
Recent history:  All 
Visits 1-3 excluding 
lifetimea
All prior history:  
Visits 1- 3 including 
lifetimea
All Visits 3.01-7
TE abnormal laboratory values
Patients in safety population with normal 
laboratory values at all nonmissing baseline visits 
(with respect to direction being analyzed) and who 
have at least 1 postbaseline observation
All Visits 1-3
All Visits 3.01-7
TE immunogenicity
Patients in safety population who are evaluable for 
TE ADA
Visit 3
All Visits 3.01-7
TE changes in vital signs and weight, ECG 
parameters
Patients in safety population with a baseline and at 
least 1 postbaseline observation
Last nonmissing
value from Visits 1-
3 for BP, pulse, and 
ECG
All Visits 1-3 for 
weight and 
temperature
Visits 3.01-7


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Patient Population with Baseline and Postbaseline Definitions by Study Phase and Type of Analysis
Study Phase/Analysis
Patient Population
Baseline 
Observation
Postbaseline 
Observation(s)
Continuous safety analysis of vital signs, weight, 
laboratory, and ECG parameters (Box-whisker 
plot)
Safety population
Last non-missing 
value from Visits 1-
3
Visits 4-7
Study Phase III and IV Combined 
TE immunogenicity
Patients in safety population who are evaluable for 
TE ADA
Visit 3
All Visits 3.01–9
Study Phase IV 
Post TEAEs
Posttreatment population
All Visits 1-7
All Visits 7.01-9
SAEs, Discontinuations due to AEs
Posttreatment population
NA
All Visits 7.01-9
C-SSRS categorical analyses
Patients in posttreatment population with a 
baseline and at least 1 postbaseline C-SSRS 
assessment
Recent history:  All 
Visits 1-7 excluding 
lifetimea
All prior history:  
Visits 1-7 including 
lifetimea
All Visits 7.01-9
Post TE abnormal laboratory values
Patients in posttreatment population with normal 
laboratory values at all nonmissing baseline visits 
(with respect to direction being analyzed) and who 
have at least 1 postbaseline observation
All Visits 1-7
All Visits 7.01-9


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Patient Population with Baseline and Postbaseline Definitions by Study Phase and Type of Analysis
Study Phase/Analysis
Patient Population
Baseline 
Observation
Postbaseline 
Observation(s)
Post TE changes in vital signs and weight, ECG 
parameters
Patients in posttreatment population and with a 
baseline and at least 1 postbaseline observation
Last nonmissing 
value from Visits 1-
7 for BP, pulse and 
ECG
All Visits 1-7 for 
weight and 
temperature
7.01-9
Abbreviations:  ADA = anti-drug antibody; AE = adverse event; BP = blood pressure; C-SSRS = Columbia Suicide Severity Rating Scale; 
ECG = electrocardiogram; ITT = intent-to-treat; NA = not applicable; SAE = serious adverse event; TE = treatment emergent; TEAE = treatment-emergent 
adverse event.
Note:  Visit 3.01 indicates the first unscheduled visit occurring after Visit 3 and prior to Visit 4.
a
Lifetime is captured in the C-SSRS Visit 1 case report form.


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5.5.2. Patient Disposition
The number and percentage of ITT patients who complete the study or discontinue early will be 
tabulated for all treatment groups for SP III and SP IV both overall and by visit. Reasons for 
discontinuation will be compared between treatment groups using Fisher’s exact test for SP III
with the ITT population. Descriptive statistics only will be presented for the treatment groups in 
SP IV.  For patients who were randomized without drug injection, reasons for early 
discontinuation will be provided in a listing.
Patient allocation by investigator will be summarized for SP III for all ITT patients.
Patient allocation by investigator will also be listed for all SPs.
5.5.3. Important Protocol Deviations
Important protocol deviations that potentially compromise the data integrity and patients’ safety 
will be summarized by treatment for the ITT population.  
Section 7 (appendix) 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 on 
Section 7 can always be added into the final nonprogrammable protocol deviations list as 
deemed necessary.
Tables and listings of subjects with important protocol deviations will be provided for the ITT 
population.
5.5.4. Patient Characteristics
The following patient characteristics at baseline will be summarized by treatment group for all 
ITT patients:

demographic (age, gender, race, ethnicity, country, region, height, weight, body mass 
index)

baseline disease characteristics:

number of weekly cluster headache attacks

average severity of cluster headache pain for the cluster headache attack days

weekly total cluster headache attack duration

weekly number of times using oxygen 

weekly number of times using oral triptan, sumatriptan nasal spray, or zolmitriptan nasal 
spray

weekly number of times using sumatriptan Sc

weekly number of times using acetaminophen/paracetamol or NSAIDs

number of times using oxygen per cluster headache attack


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
number of times using oral triptan, sumatriptan nasal spray, or zolmitriptan nasal spray
per cluster headache attack

number of times of using sumatriptan Sc per cluster headache attack

number of times using acetaminophen/paracetamol or NSAIDs per cluster headache 
attack

total weekly dose for oral triptan, sumatriptan nasal spray, and zolmitriptan nasal spray 
combined

total weekly dose for sumatriptan Sc

total weekly dose for oral triptan

total weekly dose for sumatriptan nasal spray

total weekly dose for zolmitriptan nasal spray

prior cluster headache history in last 7 days prior to Visit 1

baseline alcohol, tobacco, caffeine, and nicotine consumption

medical history and pre-existing conditions
Comparisons between treatment groups will be performed using Fisher’s exact tests for
categorical data and analysis of variance (ANOVA) with treatment and pooled investigative site 
as independent variables in the model for continuous data. 
Medical history and pre-existing conditions will be summarized by descending frequency of 
preferred term (PT) within system organ class (SOC), and by descending frequency of PT 
respectively, and comparison between treatment groups will be performed using Fisher’s exact 
test. Medical history is defined as illness(es) that ended prior to the signing of informed consent.  
Pre-existing conditions are medical events ongoing at the time of informed consent.
5.5.5. Exposure to Investigational Product
Patients will receive the investigational product (IP) at the following planned time points: 

Week 0 (Visit 3)

Week 4 (Visit 5)
The following information will be recorded on the electronic case report form (eCRF) for each 
dose: 

confirmation that the patient received the IP

date and time of administration
5.5.5.1.
Duration of Exposure
From the information recorded on the eCRF, the following will be derived: 

Duration of exposure in days calculated as Treatment End Date (disposition date in 
SP III) – First date IP administered + 1

Number and percentage of patients with 1 full dose or 2 full doses administered


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Comparisons between treatments using safety population for duration of exposure will be 
performed using an ANOVA with treatment and pooled investigative site in the model.  
The number of full doses will also be summarized. 
5.5.5.2.
Treatment Compliance
Treatment compliance will be calculated as follows
(number of full doses received)/(Number of intended full doses)*100
Note, full dose means that patients have to receive all 3 injections.  For patients that are early 
discontinued, number of intended full doses will only include scheduled doses prior to 
discontinuation.  Comparisons between treatments in the ITT population for treatment
compliance will be performed using an ANOVA with treatment and pooled investigative site in 
the model. 
5.5.6. Electronic Patient-Reported Outcome Diary Compliance
Electronic patient-reported outcome diary compliance at each weekly interval (including 
baseline, Weeks 1, 2, 3, 4, 5, 6, 7, and 8) will be calculated. Diary compliance at each interval is 
calculated as follows:
Actual number of diary entry days in the interval ∗100
Expected number of diary entry days in the interval
The diary entry can only be saved and submitted after all the required ePRO questions are 
answered, so the actual number of diary entry days represents the total number of days with non-
missing answer to all the required cluster headache attack ePRO questions.
The expected number of diary entry days is calculated as the (last calendar date - the first 
calendar date in each interval + 1).
Comparisons between diary compliance for each interval separately will be performed using an 
ANOVA with treatment and pooled investigative site in the model. 
Compliance will also be listed by weekly interval for each patient. 
5.5.7. Concomitant Therapy
The proportion of patients who received concomitant medication collected from eCRF will be 
summarized by PT separately for all ITT patients for both SP III and SP IV. Abortive 
medications for cluster headache attack collected through ePRO diary will be summarized 
separately by PT for all ITT patients for SP III.  If there are different PTs for salt forms of an
abortive medication, these PTs will be combined for the medication in the summary.  
Concomitant therapies for SP III are those that stopped during SP III or continued in SP III.  If 
medication started and stopped on the same day of first injection, it will still be considered as 
concomitant medication for SP III.  If a medication started before the first day of injection but 


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stopped on the same day of injection, then it will not be counted as concomitant medication for 
SP III.  Concomitant therapies for SP IV are those that either started, stopped, or continued in 
SP IV.
Treatment group comparisons will be done using Fisher’s exact test for SP III with the ITT 
population.  Descriptive statistics only will be presented for the treatment groups in SP IV with 
posttreatment population.
5.5.8. Efficacy Analyses
5.5.8.1.
Primary Outcome and Methodology
The primary analysis will be conducted by a REML-based, MMRM analysis using all the 
longitudinal observations from Weeks 1 to 3.  The analysis of the primary outcome will be the 
main effect of treatment between GMB 300 mg and placebo across Weeks 1 to 3 of the treatment 
phase from a repeated measures analysis on mean change from baseline in the weekly attack 
frequency. This provides the average treatment effect over the 3-week period. Baseline is 
defined as the last 7 days in the eligibility report (prerandomization diary phase).  In addition to 
the primary endpoint results, the mean profiles for GMB300mg and placebo over the 3-week 
period will also be reported from the MMRM.  
The MMRM model for the primary analysis only uses the first 3 weeks of double-blind treatment 
phase data to avoid impact of the data from later weeks when patients may start to get into the 
remission period. 
The model for the primary analysis will include the fixed, categorical effects of treatment, 
gender, pooled investigative site, week, and treatment-by-week interaction, as well as the 
continuous, fixed covariates of baseline value.  An unstructured covariance structure will be used 
to model the within-patient errors.  The Kenward-Roger (Kenward and Roger 1997) 
approximation will be used to estimate denominator degrees of freedom.  If the model does not 
converge with both the Hessian and the G matrix being positive definite under the default fitting 
algorithm used by PROC MIXED, the Fishers’ scoring algorithm will be implemented by 
specifying the SCORING option in SAS.  If the model still fails to converge, the model will be 
fit using covariance matrices of the following order specified by a decreasing number of 
covariance parameters until convergence is met: 

heterogeneous Toeplitz

heterogeneous first-order autoregressive 

Toeplitz

first-order autoregressive
If necessary, both the default and the scoring fitting algorithms will be used in the prespecified
order before proceeding to the next covariance structure in the sequence.  For models where the 
unstructured covariance matrix is not utilized, the sandwich estimator (Diggle et al. 1994) will be 
used to estimate the standard errors of the fixed effects parameters.  The sandwich estimator is 


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implemented by specifying the EMPIRICAL option in SAS.  When the sandwich estimator is 
utilized, the Kenward-Roger approximation for denominator degrees of freedom cannot be used.  
Instead, the denominator degrees of freedom will be partitioned into between-subject and within-
subject portions by the DDFM=BETWITHIN option in SAS.  SASPROC MIXED will be 
used to perform the analysis.  
5.5.8.2.
Gated Secondary
The gated secondary outcome, 50% response, is the proportion of patients meeting the response 
criteria at Week 3. A nonresponder imputation for missing values will be used.  Specifically, all 
patients who discontinue study treatment at any time prior to Week 3, for any reason, will be 
considered a nonresponder.
Treatment differences in the proportions of patients meeting 50% response definition at Week 3
will be determined using Koch’s Nonparametric Randomization-Based Analysis of Covariance 
method (Koch et al. 1998). This method will adjust for pooled investigative site by including it 
as a stratification variable and will also adjust for the continuous baseline value and gender.  A 
SAS/IML macro (NParCov3) (Zink and Koch 2012) will be used for the calculation. The 
options with this SAS/IML macro are specified in the example SAS code below. 
%NPARCOV3( outcomes =[response]
covars = [baseline] [gender]
trtgrps = [treatment]
strata = [PINVID]
hypoth = NULL
transform = NONE
combine = FIRST
c = 1
dsnin = [input]
dsnout = [output])
In this method, the option of “hypoth=NULL” indicates that the variance covariance structure
will be calculated under the assumption that the means and covariance matrices of the treatment
groups are equal and therefore computes a single covariance matrix for each stratum. The option
of “combine=FIRST” indicates that the covariate adjustment will be performed after a weighted
average of treatment group differences across pooled investigative sites to account for the
possibility of small numbers of patients at some sites. The option of “c=1” indicates the use of
Mantel-Haenszel weights for each pooled investigative site. The option of “transform=NONE”
indicates that there is not a transformation of the data.


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The analysis result of the secondary gatekeeper objective will be evaluated if the placebo versus 
GMB300mg comparison is significant for the primary efficacy analysis at a one sided α=0.025 
significance level.  
5.5.8.3.
Additional Secondary and Exploratory Efficacy Analyses
Table CGAL.5.3 summarizes all the planned additional secondary efficacy analyses for SP III
and SP IV.
For the continuous additional secondary and exploratory efficacy measures, the change from
baseline to each postbaseline period will be estimated for each treatment from repeated measures 
analyses as described in Section 5.5.8.2.  The treatment comparison at each week and overall 
across 8 weeks will be provided. As discussed in Section 5.5.1.1, for the efficacy measures that 
are not derived from cluster headache frequency, the baseline average daily cluster headache 
attack frequency category (≤4 vs. >4) will be added as a covariate in the MMRM model.
For the categorical additional secondary and exploratory efficacy measures including 30%, 50%, 
75% response, and 100% response, the percentage of patients meeting response criteria at each 
period will be estimated for each treatment from a categorical, pseudo-likelihood-based repeated 
measures analysis of visit wise binary outcomes indicating whether patients meet response
criteria. The treatment comparison at each week and overall across 8 weeks will be provided. 
This analysis will be implemented using the GLIMMIX procedure in SAS to compare treatments 
and include the fixed, categorical effects of treatment, gender, visit/week, and treatment-by-
visit/week interaction, as well as the continuous, fixed covariate of baseline value.  An 
unstructured covariance structure will be used to model the within-patient errors (denoted by 
TYPE=CHOL in the RANDOM statement). The Newton-Raphson method with ridging will be 
used for nonlinear optimization (denoted by including NLOPTIONS TECH=NRRIDG). The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom.  If the 
model does not converge, the Fishers scoring algorithm will be utilized by the SCORING option 
in SAS.  If the model still fails to converge, the model will be fit using covariance matrices in the 
following order specified by a decreasing number of covariance parameters until convergence is 
met:  heterogeneous Toeplitz, heterogeneous autoregressive, Toeplitz, and autoregressive. If 
necessary, both fitting algorithms will be used in the prespecified order before proceeding to the 
next covariance structure in the sequence.  For models where the unstructured covariance matrix 
is not utilized, the sandwich estimator (Diggle et al. 1994) will be used to estimate the standard 
errors of the fixed effects parameters.  The sandwich estimator is utilized by the EMPIRICAL 
option in SAS. When the sandwich estimator is utilized, the Kenward-Roger approximation for 
denominator degrees of freedom cannot be used. Instead, the denominator degrees of freedom 
will be partitioned into between-subject and within-subject portions by the 
DDFM=BETWITHIN option in SAS.  As discussed in Section 5.5.1.1, for the efficacy measures 
that are not derived from cluster headache frequency, the baseline average daily cluster headache 
attack frequency category (≤4 vs. >4) will be added as a covariate in the GLIMMIX model.


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Table CGAL.5.3.
Other Secondary and Exploratory Efficacy Variables and Their 
Derivation
Study Phase III
Study Phase IV
Efficacy Variable
Analyses
Change from 
baseline to each 
7-day interval 
(Weeks 1, 2, 3, 4, 
5, 6, 7, and 8)
No planned 
analysis
1.
Weekly cluster headache attack
frequency
2.
Weekly average cluster headache 
attack pain severity in the remaining 
cluster headache attack days
3.
Weekly total cluster headache attack 
duration 
4.
Weekly number of times using oxygen
5.
Weekly number of times using oral 
triptan, sumatriptan nasal spray, or 
zolmitriptan nasal spray
6.
Weekly number of times using 
sumatriptan Sc
7.
Weekly number of times using 
acetaminophen/paracetamol or 
NSAIDs
8.
Number of times using oxygen per 
cluster headache attack
9.
Number of times using oral triptan, 
sumatriptan nasal spray, or 
zolmitriptan nasal spray per cluster 
headache attack
10. Number of times using sumatriptan Sc 
per cluster headache attack
11. Number of times using 
acetaminophen/paracetamol or 
NSAIDs per cluster headache attack
12. Total weekly dose of oral sumatriptan, 
sumatriptan nasal spray and 
zolmitriptan nasal spray combined
13. Total weekly dose of sumatriptan Sc
14. Total weekly dose of oral sumatriptan 
15. Total weekly dose of sumatriptan 
nasal spray
16. Total weekly dose of zolmitriptan 
nasal spray
Variables will be analyzed by 
a repeated measures analysis 
using a model as described in 
Section 5.5.8.1 and 
Section 5.5.8.3.


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Other Secondary and Exploratory Efficacy Variables and Their Derivation
Study Phase III
Study Phase IV
Efficacy Variable
Analyses
Value at each 
visit (Visits 5, 7, 
corresponding to 
Month 1, 2)
Value at each 
visit (Visit 9,
corresponding to 
Month 6)
1.
PGI-I Score
For SP III, the variable will 
be analyzed by a repeated 
measures analysis using a 
model as described in 
Section5.5.8.3. without 
baseline covariate.
For SP IV, the variable will 
be analyzed by an ANOVA 
model as described in 
Section 5.5.1.1.
Categorical 
variables at each 
7 day period 
(Weeks 1, 2, 3, 4, 
5, 6, 7, and 8)
No planned 
analyses
1.
30% response
2.
50% response
3.
75% response
4.
100% response
5.
30% reduction in weekly total cluster 
headache attack duration
For all variables, the visit 
wise percentages of patients 
meeting criteria will be 
compared between treatments 
using a categorical, repeated 
measures analysis described 
in Section 5.5.8.3.
Categorical 
variables at each 
visit (Visits 5, 7, 
corresponding to 
Month 1, 2)
Categorical 
variables at
each visit 
(Visit 9, 
corresponding 
to Month 6)
1.
Proportion of patients reporting a 
score of 1 (“very much improved”) or 
2 (“much improved”) on Patient 
Global Impression of Improvement 
(PGI-I)
For SP III, the visit wise
percentages of patients 
meeting criteria will be 
compared between treatments 
using a categorical, repeated 
measures analysis described 
in this Section 5.5.8.3 but 
without baseline value 
covariate.
For SP IV, the Koch’s 
Nonparametric 
Randomization Based 
Analysis of Covariance 
method as described in 
Section 5.5.8.2 will be used, 
but adding the baseline 
average daily cluster 
headache attack frequency
category (≤4 vs. >4) and 
removing baseline value 
covariate.
Abbreviations:  ANOVA = analysis of variance; NSAIDs = nonsteroidal anti-inflammatory drugs; SP = study phase.
5.5.9. Safety Analyses
The safety analyses will be conducted for SP III in safety population and SP IV in posttreatment 
population.


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The safety and tolerability of treatment will be assessed by summarizing the following:

adverse events
o
treatment-emergent adverse events

by PT

by PT nested within SOC

by maximum severity
o
treatment-emergent adverse events by PT nested within SOC
o
adverse events leading to discontinuation by PT nested within SOC
o
adverse events of special interest

suicide-related thoughts and behaviors by CSSRS

vital signs and weight

laboratory measurements

electrocardiograms

antibodies (ADA and Nab)
The baseline and postbaseline for all safety measures are described in Table CGAL.5.2 unless
specified otherwise.  For SAEs, only events with a start date during the postbaseline phase will 
be accounted for the corresponding study phase analysis.
5.5.9.1.
Categorical Safety Variables
Unless specified otherwise, the categorical safety analyses will include both scheduled and 
unscheduled visits and be conducted for SP III and SP IV separately.
Comparisons between treatment groups for all categorical safety measures will be made using
Fisher’s exact test for SP III with the safety population. Descriptive statistics only will be 
presented for the treatment groups in SP IV with post-treatment population.
5.5.9.1.1.
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 CRF-collected flag will be used to determine whether the event 
was pretreatment versus posttreatment.  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 the specific postbaseline 
period. 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 


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“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 gender specific, the denominator and computation of the percentage will be 
gender adjusted.
5.5.9.1.1.1.
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 
conditions.  Only those that are judged medically to be events likely hypersensitivity in nature 
will be included in the final tables.
The number and percentage of patients with potential and/or likely TEAEs will be summarized 
by treatment groups using MedDRA PT nested within the SMQ.  Events will be ordered by 
decreasing frequency within the SMQ.  The number and percentage of patients with likely
hypersensitivity SAEs and AEs resulting in study drug discontinuation will be presented by 
treatment groups using MedDRA PT and ordered by decreasing frequency by PT.
The number and percentage of patients with likely hypersensitivity TEAEs by maximum severity
will be summarized by treatment groups using MedDRA PT.
The number and percentage of patients with likely hypersensitivity TEAEs by timing will be
summarized using MedDRA PT.  Events will be ordered by decreasing frequency of PT.  Note 
the timing of the likely hypersensitivity events is collected through eCRF and categorized into 
the following 4 categories:
1. Immediate: occurs within minutes (<60 minutes) from study drug administration
2. Acute Reaction:  occurs from 1 up to 6 hours from study drug administration
3. Delayed Reaction:  occurs from >6 hours through 14 days from study drug 
administration, which will be split into 2 categories:  on the same day of injection 
and after the day of injection
4. Reaction >14 days


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5.5.9.1.1.2.
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, SAEs related to 
injection sites, and AEs related to injection sites resulting in study drug discontinuation will be 
summarized using MedDRA PT.  Events will be ordered by decreasing frequency of PT term.
The number and percentage of patients with TEAEs related to injection sites by maximum 
severity will be summarized by treatment groups using MedDRA PT.  For each patient and 
injection site related event, the maximum severity for the MedDRA level being displayed (PT) is 
the maximum postbaseline severity observed from all associated LLTs mapping to that MedDRA 
level.
The number and percentage of patients with TEAEs related to injection sites by timing will be
summarized using MedDRA PTs ordered by decreasing frequency.  Note the timing of AEs 
related to injection sites is collected through eCRF and categorized into the same categories as 
for hypersensitivity events.
5.5.9.1.1.3.
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.  The number and percentage of patients with TEAEs of upper respiratory tract 
infections will be summarized by treatment group using MedDRA PTs.  Events will be ordered 
by decreasing frequency in the galcanezumab 300 mg group. 
The number and percentage of patients with TEAEs of upper respiratory tract infections by 
maximum severity will be summarized by treatment group using MedDRA PTs. For each 
patient and upper respiratory tract infection event, the maximum severity for the MedDRA level 
being displayed (PT) is the maximum postbaseline severity observed from all associated LLTs 
mapping to that MedDRA level.
By-subject listings of treatment-emergent upper respiratory tract infections and upper respiratory 
tract infections leading to study drug discontinuation will be provided.  
5.5.9.1.2.
Suicide-Related Thoughts and Behaviors
Postbaseline suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal 
intent occurring during SP III, based on the C-SSRS, will be summarized by treatment.  In 
particular, for each of the following events, the number and percent of patients with the event 
will be enumerated by treatment:  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.  These measures will also be 
summarized for SP IV.


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In addition, the number and percent of patients who experienced at least 1 of various composite 
measures during SP III and SP IV separately will be presented and compared.  These include 
suicidal behavior (completed suicide, nonfatal 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, nonspecific active 
suicidal thoughts, and wish to be dead), and suicidal ideation or behavior.  
The number and percent of patients who experienced at least 1 of various comparative measures 
during treatment will be presented and compared for SP III and SP IV.  These include treatment-
emergent suicidal ideation compared to recent history, treatment-emergent serious suicidal 
ideation compared to recent history, emergence of serious suicidal ideation compared to recent 
history, improvement in suicidal ideation at endpoint compared to baseline, and emergence of
suicidal behavior compared to all prior history. 
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 – Nonspecific Active Suicidal Thoughts
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 to 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 to 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 to 10) on the C-SSRS. 


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The following outcome is a numerical score derived from the C-SSRS categories.  The score is 
created at each assessment for each patient and is used for determining treatment emergence.  

Suicidal Ideation Score:  The maximum suicidal ideation category (1 to 5 on the C-SSRS) 
present at the assessment.  Assign a score of 0 if no ideation is present.
For SP III and SP IV only, comparative endpoints of interest are defined below.  “Treatment 
emergence” is used for outcomes that include events that first emerge or worsen.  “Emergence” 
is used for outcomes that include events that first emerge.  

Treatment-emergent suicidal ideation compared to recent history:  
An increase in the maximum suicidal ideation score during treatment (Visits 3.01 to 7 for 
SP III; Visits 7.01 to 9 for SP IV) from the maximum suicidal ideation category during 
the screening and lead-in periods (C-SSRS scales taken at Visits 1 to 3 excluding 
“lifetime” for SP III; C-SSRS scales taken at Visits 1 to 7 excluding “lifetime” for SP
IV).  

Treatment-emergent suicidal ideation compared to all prior history: 
An increase in the maximum suicidal ideation score during treatment (Visits 3.01 to 7 for
SP III; Visits 7.01 to 9 for SP IV) from the maximum suicidal ideation category prior to 
treatment (C-SSRS scales taken at Visits 1 to 3 including “lifetime” for SP III; C-SSRS 
scales taken at Visits 1 to 7 including “lifetime” for SP IV).  

Treatment-emergent serious suicidal ideation compared to recent history:  
An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS during 
treatment (Visits 3.01 to 7 for SP III; Visits 7.01 to 9 for SP IV) from not having serious
suicidal ideation (scores of 0 to 3) during the screening and lead-in periods (C-SSRS 
scales taken at Visits 1 to 3 excluding “lifetime” for SP III; C-SSRS scales taken at Visits 
1 to 7 excluding “lifetime” for SP IV).  

Treatment-emergent serious suicidal ideation compared to all prior history:  
An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS during 
treatment (Visits 3.01 to 7 for SP III; Visits 7.01 to 9 for SP IV) from not having serious
suicidal ideation (scores of 0 to 3) prior to treatment (C-SSRS scales taken at Visits 1 to 3
including “lifetime” for SP III; C-SSRS scales taken at Visits 1 to 7 including “lifetime” 
for SP IV).  Emergence of serious suicidal ideation compared to recent history:  

An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS during 
treatment (Visits 3.01 to 7 for SP III; Visits 7.01 to 9 for SP IV) from no suicidal ideation 
(scores of 0) during the screening and lead-in periods (C-SSRS scales taken at Visits 1 to 
3 excluding “lifetime” for SP III; C-SSRS scales taken at Visits 1 to 7 excluding 
“lifetime” for SP IV).  Recent history excludes “lifetime” scores from the Baseline C-
SSRS scale or Baseline/Screening C-SSRS scale.

Emergence of serious suicidal ideation compared to all prior history:  
An increase in the maximum suicidal ideation score to 4 or 5 on the C-SSRS during 
treatment (Visits 3.01 to 7 for SP III; Visits 7.01 to 9 for SP IV) from no suicidal ideation 
(scores of 0) prior to treatment (C-SSRS scales taken at Visits 1 to 3 including “lifetime” 
for SP III; C-SSRS scales taken at Visits 1 to 7 including “lifetime” for SP IV).  


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
Improvement in suicidal ideation at endpoint compared to baseline:
A decrease in suicidal ideation score at endpoint (the last measurement during treatment; 
Visits 3.01 to 7 for SP III; Visits 7.01 to 9 for SP IV) from the baseline measurement (the 
measurement taken just prior to that study phase (last nonmissing value taken at Visit 2 to 
Visit 3 for SP III; last nonmissing value taken at Visit 3.01 to Visit 7 for SP IV).  

Emergence of suicidal behavior compared to all prior history:  
The occurrence of suicidal behavior (Categories 6 to 10) during treatment (Visits 3.01 to 
7 for SP III; Visits 7.01 to 9 for SP IV) from not having suicidal behavior (Categories 6
to 10) prior to treatment (Visits 1 to 3 including “lifetime” for SP III; C-SSRS scales 
taken at Visits 1 to 7 including “lifetime” for SP IV). 
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.  Fisher’s exact test will be used for treatment comparisons in SP III.    
5.5.9.1.3.
Vital Signs and Weight
Vital signs collected during the study include systolic and diastolic blood pressure (SBP/DBP), 
pulse, and temperature. Blood pressure and pulse measurements will be taken when the patient 
is in a sitting position. Three measurements of sitting blood pressure and pulse will be collected 
at approximately 30- to 60-second intervals at every visit and the 3 sitting blood pressure 
measurements and 3 pulse values will be averaged and used as the value for that visit. 
Table CGAL.5.4 displays the criteria used to define treatment emergent, potentially clinically 
significant changes and sustained elevation in vital signs and weight.  The last column of the 
table displays the patient populations for each analysis based on baseline categories. The 
number and percent of patients meeting these criteria will be summarized.  Treatment group 
comparisons will be performed using Fisher’s exact test for SP III.
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 and 2) maximum postbaseline when the direction is high.

The change from baseline amount in the criteria is 1) decrease from baseline 
(defined below and in Table CGAL.5.2) to minimum postbaseline when the 
direction is low; 2) increase from baseline (defined below and in 
Table CGAL.5.2) to maximum postbaseline when the direction is high.
The baseline for SBP, DBP, and pulse is defined as the last nonmissing value during the baseline 
period (See Table CGAL.5.2).  To be exact,

The baseline for SBP, DBP, and pulse is defined as the last nonmissing value 
before randomization.  The rationale for using the last available value in the 
baseline period is to minimize the potential confound of discontinuing or dose 
stabilization of medications that modulate BP and pulse during the screening 
phase (which is early in the baseline period).


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This baseline definition for SBP, DBP, and pulse applies to all analyses (both continuous and 
categorical).
The baseline and postbaseline values for temperature and weight are defined below (also in 
Table CGAL.5.2):

For continuous analyses of temperature and weight, last nonmissing baseline 
during the baseline period will be used as the baseline value.

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 CGAL.5.4.
Criteria for Treatment-Emergent, Potentially Clinical Significant and
Categorical Changes and Sustained Elevation 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


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Criteria for Treatment-Emergent, Potentially Clinical Significant and Categorical Changes and Sustained 
Elevation in Vital Signs and Weight
Parameter
Direction
Criteria
Patients Population 
Defined by Baseline 
Categories
Temperature (F)
Low
<96F and decrease ≥2F
96F
High
≥101F and increase ≥2F
<101F
Abbreviations:  BP = blood pressure; PCS= Potentially Clinically Significant; mm Hg = millimeters of mercury; 
bpm = beats per minute; kg = kilograms; F = degrees Fahrenheit.  
5.5.9.1.4.
Electrocardiogram Intervals and Heart Rate
Analyses of corrected QT (QTc) interval and 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.  A listing of ECG data for patients with 
QRS ≥120 milliseconds at any time during the study will be provided. 
The baseline for ECG is defined as the last nonmissing baseline value during the baseline period.  
To be exact,

The baseline for ECG is defined as the last nonmissing value before randomization.  
The rationale for using the last available value in the baseline period is to minimize 
the potential confound of discontinuing or dose stabilization of medications that 
modulate ECG during the screening phase (which is early in the baseline period).
This baseline definition for ECG applies to all analyses (both continuous and categorical,
quantitative and qualitative).
The baseline and postbaseline values are summarized in Table CGAL.5.2. 
The number and percent of patients meeting criteria for treatment-emergent abnormalities in 
ECG intervals (PR, QRS, and QTcF) and heart rate at any time during study will be summarized.
Treatment group comparisons will be performed using Fisher’s exact test for SP III.  
Table CGAL.5.5 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 1
postbaseline result will be included. 


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Table CGAL.5.5.
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
>500 msec
Increase
Increase >30 msec
Increase >60 msec
Increase >75 msec
Abbreviations:  bpm = beats per minute; ECG = electrocardiogram; PCS = Potentially 
Clinically Significant; QTcF = Fridericia’s corrected QT interval.


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In addition, qualitative ECG abnormalities will be evaluated that will include summaries of 11 
ECG categories (Axis, Rhythm, Conduction, Ischemia, Infarction, Injury, Morphology, U-waves, 
T-waves, ST Segment, and Other Abnormalities) of qualitative findings at any time postbaseline. 
A category is a collection of possible descriptions (findings) of 1 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 1 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.
The summaries of the 11 ECG categories will exclude ECGs with any of the following:  overall 
ECG could not be evaluated by the cardiologist, lead reversals or <9 leads, nonmatching 
demographic data, and those suggesting patient identification errors.
5.5.9.1.5.
Laboratory Tests
The incidence rates of patients with treatment-emergent abnormal, high, or low laboratory values 
for each laboratory test based on Covance reference ranges at any time postbaseline will be 
summarized.  The baseline and postbaseline definitions are summarized in Table CGAL.5.2.  
The treatment comparisons will be assessed using Fisher’s exact tests for SP III.
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.
The incidence of patients with the following elevations in hepatic laboratory tests at any time 
postbaseline will also be summarized and comparison between treatment groups for SP III using 
Fisher’s exact test.  

The percentages of patients with an alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) measurement greater than or equal to 3 times (3), 5 times (5), 
and 10 times (10) the Covance upper limit of normal (ULN) during the treatment period 
will be summarized for all patients with a postbaseline value.  


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
The percentages of patients with an alkaline phosphatase (ALP) greater than or equal to 
2 times (2) the Covance ULN during the treatment period will be summarized for all 
patients with a postbaseline value.  

The percentages of patients with a total bilirubin (TBIL) measurement greater than or 
equal to 2 times (2) ULN during the treatment period will be summarized for all patients 
with a postbaseline value.
The analysis of elevation in ALT, AST, ALP, and TBIL will contain 3 subsets:  

patients whose nonmissing maximum baseline value is less than or equal to 1ULN for 
ALT, AST, ALP, and TBIL.

patients whose nonmissing maximum baseline value is greater than 1ULN for ALT, 
AST, ALP, and TBIL, and at the same time less than or equal to 2ULN for ALT and 
AST, 1.5ULN for ALP and TBIL.  

patients whose nonmissing maximum baseline value is greater than 2ULN for ALT and 
AST, 1.5ULN for ALP and TBIL.
A listing of patients who had met any following criteria postbaseline will be provided over all 
study phases:  ALT≥3ULN, or AST ≥3ULN, or ALP ≥2ULN, or TBIL≥2ULN. 
5.5.9.1.6.
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 galcanezumab concentration.  Thus, a GMB drug concentration, 
assessed from 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.
5.5.9.1.6.1.
Definitions of Sample Anti-drug Antibody Status
Table CGAL.5.6 and Table CGAL.5.7 list sample ADA assay results and clinical interpretation 
of the sample results.


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Table CGAL.5.6.
Sample ADA Assay Results
Sample Laboratory Result
Explanation
Detected
ADA are detected and confirmed.
Not Detected
The raw result as reported from the laboratory indicates not detected.  The clinical 
interpretation of such results depends other factors (see below).
No Test, QNS, etc.
Sample exists but was unevaluable by the assay
Abbreviation:  ADA = anti-drug antibody.
Table CGAL.5.7.
Sample Clinical ADA Interpretation Results
Sample Laboratory Result
Explanation
ADA Present
ADA assay result detected.
ADA Not Present
ADA assay result is Not Detected and simultaneous drug concentration is at a level 
that has been demonstrated to not interfere in the ADA detection method (i.e., drug 
concentration is below the assay's drug tolerance level). 
For patients receiving placebo, drug concentration is not assessed and is assumed to 
be below the assay's drug tolerance level.
ADA Inconclusive
ADA assay result is Not Detected but drug concentration in the sample is at a level 
that can cause interference in the ADA detection method.
ADA Not Detected with Drug 
Concentration Not Available
If drug concentration analysis was planned but result is not available for a 
treatment-period sample, a Not Detected sample will be declared ADA Not 
Detected with Drug Concentration Not Available.
In the computation of Patient ADA status (see below, Section5.5.9.1.6.2), these 
samples will be considered ADA Not Present, on the basis of prior knowledge that 
the drug tolerance level of the ADA assay is high relative to the expected drug 
concentration levels.
ADA Missing
ADA sample not drawn, QNS, not tested, etc., causing there to be no laboratory 
result reported or the result is reported as “no test”.
Abbreviation:  ADA = anti-drug antibody. 
Parallel terminology applies for NAb Detected, NAb Not Detected, NAb Present, NAb Not 
Present, NAb Inconclusive, NAb Not Detected with Drug Concentration Not Available, and 
NAb Missing.  Anti-drug antibody and NAb are distinct assays and have different assay-
operating characteristics.
5.5.9.1.6.2.
Definitions of Patient Anti-drug Antibody Status
Patient evaluable for TE ADA:  A patient is evaluable for TE ADA if the patient has a 
nonmissing baseline ADA result and at least 1 nonmissing postbaseline.
TE ADA positive (TE ADA+) patient:  A patient who is evaluable for TE ADA is TE ADA+ if 
either of the following holds:


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
Treatment-induced:  The patient has baseline status of ADA Not Present and 
at least one postbaseline status of ADA Present with titer ≥20 (ie, 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 1 postbaseline status of ADA Present, with titer 1:P, with 
P/B ≥4.  
TE ADA Inconclusive patient: A patient who is evaluable for TE ADA is TE ADA 
Inconclusive if ≥20% of the patient’s postbaseline samples, drawn predose, are ADA 
Inconclusive and the patient is not otherwise TE ADA+.
TE ADA negative (TE ADA-) patient:  A patient who is evaluable for TE ADA is TE ADA-
when the patient is not TE ADA+ and the patient is not TE ADA Inconclusive. 
5.5.9.1.6.3.
Analyses to Be Performed
To evaluate the changes in immunogenicity data (Anti-galcanezumab [ADA and NAb]) after 
treatment, the number and proportion of patients who are TE ADA+ will be tabulated where 
proportions are relative to the number of patients who are TE ADA evaluable as defined in 
Section 5.5.9.1.6.2).  The baseline and postbaseline definitions for each analysis period is shown 
in Table CGAL.5.2.  In detail the following statistical analyses for each immunogenicity analyte 
(ADA and NAb) are planned:  

the incidence of TE ADA will be summarized as follows:
o
for safety population during double-blind treatment phase and 
compared between treatment arms using Fisher’s exact test
o
for the ADA follow-up cohort during double-blind treatment phase, 
the ADA follow-up cohort is defined as patients in the safety 
population with ADA assessment during post-treatment phase
o
for the ADA follow-up cohort during double-blind treatment phase 
and post-treatment phase

shift from baseline to maximum postbaseline ADA titers for the 
galcanezumab-treated patients during double-blind treatment phase

summary of time to first TE ADA+ titer during double-blind phase
The following descriptive listings will also be provided:

listing of patients with TE ADA at any time during study, NAb Status will 
also be displayed

listing of patients with inconclusive ADA or inconclusive NAb at any time


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
listing of patients with ADA present at any time or TE hypersensitivity events 
or TEAEs related to injection sites.
5.5.9.2.
Continuous Safety Measures
Analyses of continuous safety data will be conducted on patients who have a baseline and at least 
1 postbaseline observation for SP III.
For all the continuous safety measures (including planned laboratory measures, vital signs and 
weight, ECG intervals and heart rate), box-whisker plots with summary statistic tables for 
absolute value and change from baseline at scheduled visit and at endpoint (defined as the final 
postbaseline value) will be provided for SP III. The change from baseline results will be 
compared between treatment arms using the analysis of covariance (ANCOVA) model with 
treatment, pooled investigative site and baseline value in the model.
5.5.10. Subgroup Analyses
Subgroup analyses will be performed for primary efficacy measure (change from baseline on 
weekly number of cluster headache attack) only for the ITT patients in the SP III. 
Table CGAL.5.8 provides definitions for each subgroup variable.  Subgroup variables are 
usually selected if they are potentially prognostic or predictive.  A subgroup variable is 
prognostic if values of the subgroup variable predict the change in efficacy measures regardless 
of the treatment group assignment.  A subgroup variable is predictive if values of the subgroup 
variable predict heterogeneous treatment effect.  Demographic subgroup variables (sex, racial 
origin, ethnicity, age, and region) may neither be prognostic nor predictive, but they are standard 
subgroup variables needed for regulatory submission.  Baseline average daily number of cluster 
headache attack category and sex were included in the dynamic allocation randomization 
algorithm and are considered possibly prognostic.
  
The purpose of the analyses for these subgroup variables is to assess the consistency of treatment 
effects across the different values of each subgroup variable.  
Table CGAL.5.9 summarizes the subgroup analyses to be conducted, using those subgroup 
variables presented in Table CGAL.5.8.
Table CGAL.5.8.
Definition of Subgroup Variables
Subgroup Variable
Categories
Sex
Male, female
Racial origin (combine those with less than 
10%)
American Indian/Alaskan Native
Asian
Black/African American
Native Hawaiian/Pacific Islander
White
Multiple
Ethnicity
Hispanic or Latino
Not Hispanic or Latino
Age
<40 or ≥40
CCI


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Definition of Subgroup Variables
Subgroup Variable
Categories
Baseline average daily number of cluster 
headache  attack category
1) ≤4 attack per day, >4 attack per day
2) ≤3 attacks per day, >3 attacks per day
3) ≤2 attacks per day, >2 attacks per day
Region
Europe, North America (US and Canada)
Table CGAL.5.9.
Subgroup Analyses
Outcome Variable
Subgroup Variables
Analysis
EFFICACY VARIABLES
1. Change from baseline to each 
postbaseline weekly interval up to 
Week 3 in the SP III for:
Number of cluster headache attacks
Sex
Racial origin
Ethnicity
Age
Baseline average daily number of 
cluster headache attack category
Region 
Repeated measures analysis using 
the model described in 
Section 5.5.8.1 with additional
terms for subgroup, subgroup-by-
treatment, subgroup-by-week, and 
subgroup-by-treatment-by-week
interactions added to the base 
model.  
Abbreviations:  
SP = study phase.
For the subgroup variable of race, all the categories that have less than 10% of the patients in the 
study will be combined in the analysis.
 
For subgroup analyses, the 
subgroup-by-treatment and subgroup-by-treatment-by-visit/week interactions will be tested at a 
2-sided 0.05 significance level.  Treatment group differences will be evaluated within each 
category of the subgroup variable.
The subgroup analysis for change from baseline to each weekly interval up to Week 3 in number 
of cluster headache attacks will be conducted with repeated measures analysis. The same 
MMRM model as described in Section 5.5.8.1 will be used with additional terms of subgroup, 
subgroup-by-treatment, subgroup-by-week, and subgroup-by-treatment-by-week interactions 
added.  In this analysis, the p-value for the subgroup-by-treatment, subgroup-by-week, and 
subgroup-by-treatment-by-week interactions will be reported.
For subgroup analysis, the LSMean and LSMean change estimate as well as the treatment 
comparisons within each subgroup will be analyzed with the data within that specific subgroup 
only.
CCI
CCI
CCI
CCI


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5.5.11. Sensitivity Analysis 
For all sensitivity analyses for the primary efficacy endpoint, the diary data up to Week 3 will be 
used. 
Dynamic Allocation (Minimization) Assumption 
A permutation test will be performed as a sensitivity analysis of the primary MMRM analysis to 
confirm the results of the asymptotic inference.  The key features of the permutation test that will 
be employed are as follows:   
 The patients’ baseline covariates, responses, and enrollment order will be considered 
fixed. 
 The sharp null hypothesis will be assumed, i.e., responses to galcanezumab and 
placebo will be assumed exactly equal. 
 The exact minimization algorithm and exact site pooling algorithm will be used to 
generate the null distribution of the primary test statistic from the MMRM analysis. 
 The p-value based on the generated null distribution (i.e., permutation test p-value) 
will be obtained by comparing the observed test statistic value to the percentiles of 
the generated null distribution. 
Explicitly, the p-value is derived from the permuted distribution of test statistics as follows.  If 
the total number of permutations is ݉, and ܾ of these permutations have a test statistic greater 
than or equal to the observed test statistic, ݖ, then the permutation p-value, ݌௣ is, 
݌௣ൌܾ൅1
݉൅1 
where ݉ equals 100 000.  As discussed in Phipson and Smith (2010), this is an upper bound on 
the estimated p-value.  This method is used to generate the approximate null distribution.  Note 
that the described permutation p-value calculation should be conducted such that a positive value 
for the test statistic should indicate a favorable treatment effect galcanezumab 300 mg relative to 
placebo. 
Missing Data Assumption 
Sensitivity analyses will be performed to assess the robustness of the primary analysis 
conclusions to deviations from MAR assumption.  The approach for these analyses is to vary the 
assumptions of missing data for the primary analysis in a systematic way.  Basically, the method 
will be to predict the missing outcomes and then add a value (denoted as ΔA) to the predictions in 
the active treatment group and another value (denoted as ΔP) to the predictions in the placebo 
treatment group, consistent with the sensitivity approach suggested in Permutt (2015).  This 
procedure will be repeated multiple times for different values of (ΔA, ΔP) using the following 
steps:   


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1. Predict the missing outcomes for each treatment via multiple imputation based 
on observed primary endpoint and baseline values.  Such imputation will be 
carried out using a Markov Chain Monte Carlo method with a Jeffreys prior
via SAS® PROC MI.  Thirty (30) such imputations will be created. 
2. Add ΔA to the imputed values for patients taking active treatment and ΔP to 
the imputed values for patients taking placebo. 
3. Conduct the primary analysis separately for each of the 30 imputations.
4. Combine the results of these analyses using Rubin’s combining rules, as 
implemented in SAS® PROC MI ANALYZE.
The above steps will be repeated multiple times for different values of (ΔA, ΔP) with 
ΔP ranging from (0, twice the absolute value of the mean value seen for placebo in the primary 
analysis) and ΔA ranging from (ΔP, ΔP + absolute value of the mean treatment difference seen 
within the primary analysis).  For example, if the mean change from baseline for placebo is -3.6 
and the corresponding treatment difference is -1.5, then ΔP would range from (0, 7.2) and ΔA
would range from (ΔP, ΔP + 1.5).
Normality Assumption
To assess the robustness of the MMRM results to deviations from normality assumption, a 
sensitivity analysis for raw number of cluster headache attacks (total number of cluster headache 
attacks for each interval without imputing missing value and without normalization to 7-day 
period) will be conducted with a repeated measures negative binomial regression model fitted 
with SAS PROC GLIMMIX.  The model will include treatment, gender, pooled investigative 
site, weekly time period (Week 1, Week 2, Week 3), and treatment-by-time-period interaction, as 
well as the continuous fixed covariates of baseline value, and log (number of compliant days 
within each weekly time period divided by 7) as the offset in the model.  In case of 
nonconvergence, pooled investigative site may be excluded from the model.  Directional 
consistency of treatment effects from this model and the primary analysis MMRM model as 
specified in Section 5.5.8.1 will be examined.
In addition, as another form of sensitivity analysis, residuals from the primary analysis MMRM 
model will be examined and outliers identified.  Consistency of results before and after removing 
patients with outlier residuals will be examined.
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5.6.
Interim Analyses
Up to 2 interim analyses were planned for Study CGAL. Interim analysis 1 during SP III may be 
conducted that may result in increasing the sample size or stopping the trial for futility.  Details 
were documented in the Statistical Analysis Center SAP, ERB supplement, and DMC Charter.  
However, this interim analysis for sample size re-estimation will not happen due to enrollment 
infeasibility.  The DMC will still independently monitor patient safety during this trial.
The other interim analysis that was planned will be conducted after all patients have had the 
opportunity to complete 8 weeks of treatment (SP III) and, thus, will be the final analysis of 
the primary efficacy endpoint.  The interim analysis will be conducted using internal 
unblinded study team members who do not have direct interaction with sites.
5.7.
Unblinding Plan
Interim analysis will be conducted by unblinded study team members who do not have direct 
interaction with sites.  All study personnel with direct interaction with sites are kept blinded to
individual patient treatment information.
5.8.
Reports to Be Generated at Each Interim and Final Database 
Lock
5.8.1.1.
Reports to Be Generated at Interim Database Lock
For the interim analysis, the database will be locked after all randomized patients have had the 
chance to complete 8 weeks of treatment in SP III.  However, some patients will still be ongoing 
in SP IV at the time of the database lock.  Data up to the data cutoff date in the locked database 
from all study phases will be used, and analyses specified in this SAP will be performed.  
However, only analyses conducted for SP III at interim analysis will be considered as the final 
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analyses.  The analyses including data from SP IV will be rerun and updated when the completed 
data are available at the final database lock.
5.8.1.2.
Reports to Be Generated at Final Database Lock
For final database lock, all analyses including tables, figures and listings that use data from SP 
IV will be generated. 
5.9.
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 treatment group and 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 and treatment group, 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 every 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.


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6.
References
Diggle P, Liang K, Zeger S. Analysis of longitudinal data. Oxford: Clarendon Press; 1994.
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.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53(3):983-997.
Koch GG, Tangen CM, Jung JW, Amara IA. Issues for covariance analysis of dichotomous and
ordered categorical data from randomized clinical trials and non-parametric strategies for
addressing them. Stat Med. 1998;17(15-16):1863-1892.
Mallinckrodt CH, Lane PW, Schnell D, Peng Y, Mancuso J. Recommendations for the primary 
analysis of continuous endpoints in longitudinal clinical trials. Drug Information Journal.
2008;42(4):303-319.
Permutt T. Sensitivity analysis for missing data in regulatory submissions. Stat 
Med. 2015;35(17):2876-2879.
Phipson B, Smyth GK. Permutation p-values should never be zero: calculating exact p-values 
when permutations are randomly drawn. Stat Appl Genet Mol Biol. 2010; 9:Article39.
Pocock S, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
controlled clinical trial. Biometrics. 1975;31(1):103-115.
The Sumatriptan Cluster Headache Study Group. Treatment of acute cluster headache with 
sumatriptan. N Engl J Med. 1991;325(5):322-326.
Zink RC, Koch GG. NParCOV3: a SAS/IML macro for nonparametric randomization based 
analysis of covariance. J Stat Softw. 2012;50(3):1-17.


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7.
Appendices


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Appendix 1.
Description of Important Protocol Deviations
Category
Subcategory
Study Specific Term
Source
Informed 
Consent
Form (ICF)
Informed 
consent not 
obtained 
Programmable 
Improper
consent
ICF not signed prior to 
initiation of protocol 
procedures
Nonprogrammable 
Eligibility
Inclusion/
Exclusion
At Visit 1 patients must 
have a history of episodic
cluster headache
Nonprogrammable 
Age < 18 or > 65 years 
old at study entry
Nonprogrammable
Female patients who have 
a positive serum 
pregnancy test prior to 
Visit 3
Programmable
Randomized patients had 
prior or current exposure 
to CGRP antibody
Nonprogrammable 
Corrected QT (QTcB) 
interval > 470 msec for 
women and >450 for men 
prior to Visit 3
Nonprogrammable 
PR > 220, or conduction 
delay of QRS>120 prior 
to Visit 3
Nonprogrammable 
SBP >160 mm Hg or 
DBP >100 mm Hg on 2 
or more blood pressure 
assessments prior to Visit 
3
Programmable
Evidence of ischemia 
/qualitative findings of 
ST or J-point elevation, 
excluding early 
repolarization
Nonprogrammable 
History of MI, UA, PCI, 
CABG, or DVT/PE 
within 6 months of 
screening
Nonprogrammable 
Have planned 
cardiovascular surgery or 
percutaneous coronary 
angioplasty
Nonprogrammable


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Category
Subcategory
Study Specific Term
Source
Eligibility
Inclusion/
Exclusion
Any lifetime history of 
vasospastic angina or 
stroke
Nonprogrammable
Clinical evidence of 
peripheral vascular 
disease or a diagnosis of 
Raynaud’s Phenomenon
Nonprogrammable 
Have any history of 
intracranial or carotid 
aneurysm, intracranial 
hemorrhage, stroke
Nonprogrammable 
Have a history of 
intracranial tumors or 
significant head trauma 
that preclude study 
participation
Nonprogrammable
Have a clinically 
significant elevation of ≥2
X ULN for ALT, or ≥1.5
X ULN for TBIL or ALP 
prior to V3
Nonprogrammable
Have a positive urine drug 
screen for substances of 
abuse not allowed prior to 
randomization
Programmable 
Completion of less than 5 
of 7 days of the daily 
ePRO diary during the 
baseline assessment
Programmable
Baseline weekly cluster 
headache attack:  (a) ≥2 
consecutive days without 
attack, or (b) <4 total 
attacks, or (c) >8 attacks 
per day
Programmable
Body mass index (BMI) 
≥40 kg/m2 at baseline.
Programmable
Use within 14 days prior 
to SP II or in SP II/III of 
any of the medications 
described in I/E 9a
Programmable
Use within 30 days prior 
to SP II or in SP II/III of 
any of the medications 
described in I/E 9b
Programmable


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Category
Subcategory
Study Specific Term
Source
Study 
Procedures
Other
Use of Botox within 4 
month prior to SP II and 
during study
nonprogrammable
Use of other excluded 
meds during study
Nonprogrammable
Use of verapamil at doses 
higher than allowed at 
baseline and during study
Programmable 
Missing any scheduled or 
unscheduled C-SSRS
Programmable 
Missing all triplet 
measurements of blood 
pressure or pulse at any 
scheduled visit
Programmable 
Missing entire chemistry 
or hematology panel
Programmable 
No ECG measurements 
during a study phase
Programmable 
Investi-
gational 
Product
Patient took 
medication not 
fit for use
Nonprogrammable
Unblinding
NonProgrammable
Other
IP lost or stolen
Nonprogrammable 
Dose planned but not 
given–date of injection 
missing
Programmable
Dosing interval outside 
specified limits of 21-37 
days for double-blind 
treatment phase
Programmable 
Dosing Error
Nonprogrammable 
Safety
SAEs
Nonprogrammable 
Other
Positive pregnancy test
Nonprogrammable 
Data 
Quality
Treatment 
Assignment/
Randomization 
Error
IWRS data entry errors 
that impact patient 
stratification
Programmable
Treatment 
Assignment/Ran
domization Error
Randomized after 
screening failure, no study 
drug dispensed
Programmable


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Category
Subcategory
Study Specific Term
Source
Data 
Quality
Other
Primary efficacy 
compliance rate ≤50% in 
any weekly interval 
during DB treatment 
phase
Programmable
Data Entry
Issues
Patients did not report 
oxygen use in number of 
times in eDiary
nonprogrammable
Admini-
strative 
Oversight
Patient Privacy 
Violation
Nonprogrammable
Suspected 
Misconduct
Nonprogrammable
Other
Post training; switching 
roles blinding to 
unblinded vice versa 
without prior medical 
team approval
Nonprogrammable 
Unqualified or untrained 
site personnel administer 
(C-SSRS)
Nonprogrammable
Quality issue at site or 
vendor
Nonprogrammable
Abbreviations:  ALT = alanine aminotransferase; ALP = alkaline phosphatase; BMI = body mass index; CABG = 
coronary artery bypass grafting; C-SSRS = Columbia-Suicide Severity Rating Scale; DBP = diastolic blood 
pressure; DVT = deep vein thrombosis; ECG = electrocardiogram; ePRO = electronic patient-reported outcome; 
ICF = informed consent form; I/E = inclusion/exclusion criteria; IP = investigational product; IWRS = interactive 
web-response system; MI = myocardial infarction; PCI = percutaneous coronary intervention; PE = pulmonary 
embolism; PR = pulse rate; SAE = serious adverse event; SBP = systolic blood pressure; SP = study phase; TBIL 
= total bilirubin; UA = unstable angina; ULN = upper limit normal. 


Leo Document ID = 6d5b9e94-d91f-45f5-8bbd-335b57713af7
Approver: 
Approval Date & Time: 05-Apr-2018 19:35:35 GMT
Signature meaning: Approved
PPD