Clinical trial NCT04294147
Conditions: Migraine
Keywords: prevention prophylaxis headache
Sponsor: Eli Lilly and Company
Start date: 2020-10-06; Completion date: 2021-03-05
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to measure the gastrointestinal emptying time using the wireless motility capsule (WMC) technology (FDA approved SmartPill™) in adult participants with migraine who are taking a monoclonal antibody (mAb) calcitonin gene-related peptide (CGRP) antagonist called galcanezumab or erenumab.

Detailed description:

Arms: arm 1: Participants received a single subcutaneous (SC) dose of 240 milligram (mg) Galcanezumab. arm 2: Participants received a single SC dose of 140 mg Erenumab.
Interventions: intervention 1: Galcanezumab intervention 2: Erenumab
Intervention descriptions: intervention 1: Administered SC intervention 2: Administered SC

Protocol documents:
Prot_000.pdf: 
 
 
 
Protocol: I5Q-MC-CGBC (a)  
 
 
A Phase 4 Single-Blind Study of Gastrointestinal Transit Time in 
Adult Patients with Migraine Before and After Initiation of a mAb 
CGRP Antagonist. 
 
 
NCT04294147 
 
 
Approval Date: 19-May-2020 


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galcanezumab (LY2951742)
Protocol I5Q-MC-CGBC
A Phase 4 Single-Blind Study of Gastrointestinal Transit 
Time in Adult Patients with Migraine Before and After 
Initiation of a mAb CGRP Antagonist
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
galcanezumab, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure. Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release. In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
galcanezumab-gnlm (LY2951742)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on 15 November 2019
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 19-May-2020 GMT


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Table of Contents
Section
Page
Protocol I5Q-MC-CGBC A Phase 4 Single-Blind Study of 
Gastrointestinal Transit Time in Adult Patients with Migraine Before 
and After Initiation of a mAb CGRP Antagonist .................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................12
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................17
4.
Objectives and Endpoints..................................................................................................19
5.
Study Design.....................................................................................................................21
5.1.
Overall Design .............................................................................................................21
5.2.
Number of Participants.................................................................................................22
5.3.
End of Study Definition ...............................................................................................22
5.4.
Scientific Rationale for Study Design...........................................................................22
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................24
6.3.
Lifestyle Restrictions....................................................................................................26
6.4.
Screen Failures.............................................................................................................26
7.
Treatments........................................................................................................................27
7.1.
Treatments Administered .............................................................................................27
7.1.1.
Packaging and Labeling .......................................................................................27
7.1.2.
Medical Devices...................................................................................................27
7.2.
Method of Treatment Assignment ................................................................................28
7.2.1.
Selection and Timing of Doses.............................................................................28
7.3.
Blinding .......................................................................................................................28
7.4.
Dosage Modification....................................................................................................28
7.5.
Preparation/Handling/Storage/Accountability...............................................................28
7.6.
Treatment Compliance .................................................................................................29
7.7.
Concomitant Therapy...................................................................................................29
7.8.
Treatment after the End of the Study............................................................................29


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8.
Discontinuation Criteria ....................................................................................................30
8.1.
Discontinuation from Study Treatment.........................................................................30
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................30
8.1.2.
Temporary Discontinuation from Study Treatment...............................................30
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................30
8.2.
Discontinuation from the Study....................................................................................30
8.3.
Lost to Follow-Up........................................................................................................31
9.
Study Assessments and Procedures ...................................................................................32
9.1.
Efficacy Assessments...................................................................................................32
9.1.1.
Primary Assessment of GI Transit Time...............................................................32
9.1.2.
Secondary Assessment Scales ..............................................................................32
9.1.3.
Appropriateness of Assessments ..........................................................................32
9.2.
Adverse Events ............................................................................................................32
9.2.1.
Serious Adverse Events........................................................................................33
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................34
9.2.2.
Complaint Handling.............................................................................................35
9.3.
Treatment of Overdose.................................................................................................35
9.4.
Safety...........................................................................................................................35
9.4.1.
Vital Signs ...........................................................................................................35
9.4.2.
Laboratory Tests ..................................................................................................35
9.4.3.
Immunogenicity Assessments ..............................................................................35
9.4.4.
Safety Monitoring ................................................................................................35
9.4.4.1.
Hepatic Safety Monitoring..............................................................................35
9.5.
Pharmacokinetics .........................................................................................................35
9.6.
Pharmacodynamics ......................................................................................................35
9.7.
Genetics .......................................................................................................................35
9.8.
Biomarkers...................................................................................................................36
9.9.
Health Economics ........................................................................................................36
10.
Statistical Considerations ..................................................................................................37
10.1. Sample Size Determination ..........................................................................................37
10.2. Populations for Analyses..............................................................................................37
10.3. Statistical Analyses ......................................................................................................37
10.3.1.
General Statistical Considerations ........................................................................37
10.3.2.
Treatment Group Comparability...........................................................................38
10.3.2.1.
Patient Disposition..........................................................................................38
10.3.2.2.
Patient Characteristics ....................................................................................38
10.3.2.3.
Concomitant Therapy .....................................................................................38
10.3.2.4.
Treatment Compliance....................................................................................38


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10.3.3.
Efficacy Analyses ................................................................................................38
10.3.3.1.
Primary Analyses ...........................................................................................38
10.3.3.2.
Secondary Analyses........................................................................................38
10.3.3.3.
Tertiary/Exploratory Analyses ........................................................................39
10.3.4.
Safety Analyses....................................................................................................39
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................39
10.3.6.
Evaluation of Immunogenicity .............................................................................40
10.3.7.
Other Analyses.....................................................................................................40
10.3.7.1.
Health Economics...........................................................................................40
10.3.7.2.
Subgroup Analyses.........................................................................................40
10.3.8.
Interim Analyses..................................................................................................40
11.
References ........................................................................................................................41
12.
Appendices .......................................................................................................................44


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List of Tables
Table
Page
Table CGBC.2.1.Schedule of Activities....................................................................................13
Table CGBC.4.1.Objectives and Endpoints...............................................................................19
Table CGBC.7.1.Treatment Regimens......................................................................................27


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List of Figures
Figure
Page
Figure CGBC.3.1. Mechanism of action of CGRP monoclonal antibodies................................17
Figure CGBC.5.1. Illustration of study design for Clinical Protocol I5Q-MC-CGBC................21


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................45
Appendix 2.
Study Governance Considerations..................................................................48
Appendix 3.
Protocol Amendment
I5Q-MC-CGBC(a) Summary
A Phase 4 Single-Blind Study of Gastrointestinal Transit Time in 
Adult Patients with Migraine Before and After Initiation of a mAb 
CGRP Antagonist........................................................................................53


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1. Synopsis
Title of Study:
A Phase 4 single-blind study of gastrointestinal transit time in adult patients with migraine before 
and after initiation of a mAb CGRP antagonist.
Rationale:
Differences have been observed between reported frequencies of constipation in clinical trials
and postmarketing adverse event (AE) reporting among calcitonin gene-related peptide (CGRP) 
antagonists. In particular, these differences have been observed between CGRP monoclonal 
antibodies (mAb) that target the ligand (galcanezumab, fremanezumab) or the receptor 
(erenumab) for the prevention of migraine (Stauffer et al. 2018b; Ashina et al. 2019; FDA
[WWW] 2019; Robbins 2019; Silberstein et al. 2019; Aimovig package insert, 2020).  
Preclinical animal studies suggest that differences in the mechanism of action of these agents 
may contribute to the different frequencies of constipation (Hargreaves and Olesen 2019).  The 
purpose of Study I5Q-MC-CGBC (CGBC) is to measure gastrointestinal (GI) transit time in 
adult patients with migraine who have been initiated on preventive treatment with a CGRP 
antagonist (galcanezumab or erenumab), and explore whether there is a mechanistic difference 
that contributes to GI AEs in humans.
A wireless motility capsule (WMC) technology will be used to evaluate total GI transit time as 
well as segmental transit time. The US Food and Drug Administration has approved the WMC 
(SmartPill™) for the evaluation of adult patients with suspected delayed gastric emptying and 
the evaluation of colonic transit time (CTT) and combined small and large bowel transit time 
(SLBTT) in patients with chronic constipation (Saad and Hasler 2011; Medtronic 2017).
Components to the WMC system include a WMC (SmartPill™Motility Capsule), a wearable 
data recorder (SmartPill™Motility Recorder), and a software program (MotiliGI™). The 
system measures whole gut and regional (stomach, small bowel, and colon) transit time by 
measuring pressure, pH, and temperature throughout the GI tract (Medtronic 2017). The 
American and European Neurogastroenterology and Motility Societies recognized the WMC 
technology as a validated, standardized, objective measure of GI transit time and recommended 
its use for testing in individuals with suspected alterations of GI motility (Rao et al. 2011).


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Objectives/Endpoints:
Objectives
Endpoints
Primary Objective
To evaluate colonic transit time (CTT) in patients 
with migraine 1 week prior to and 2 weeks after
administration of an initial loading dose of 
galcanezumab 240 mg or erenumab 140 mg.
Change from baseline in CTT after administration of 
galcanezumab or erenumab within each treatment group in 
hours at the end of Week 2.
Secondary Objectives
To evaluate transit time of the following segments 
of the gastrointestinal (GI) tract 1 week prior to and 
2 weeks after administration of galcanezumab or 
erenumab:

whole gut

gastric emptying

small bowel

combined small and large bowel.
Change from baseline in GI transit time in each of the 
following segments after administration of galcanezumab 
or erenumab within each treatment group at the end of 
Week 2:

Whole gut transit time (WGTT) in hours

Gastric emptying time (GET), in hours

Small bowel transit time (SBTT), in hours

Combined small and large bowel transit time 
(SLBTT), in hours.
To evaluate the frequency of contractions, motility 
index, and area under the pressure curve (AUC) by 
quartile in the colon to assess for correlation with 
CTT results.
Changes in pressure parameters from baseline:

Contraction Freq/Min

Motility Index =  ln (# of contractions x 
∑pressure amplitudes +1)  

Area under the Pressure Curve.
To evaluate number of weekly spontaneous bowel 
movements (un-aided by laxatives, enemas, or 
suppositories) prior to and after administration of 
galcanezumab or erenumab.
Change from baseline in number of weekly spontaneous 
bowel movements after administration of galcanezumab or 
erenumab within each treatment group at Weeks 2 and 4.
To evaluate GI symptom rating scale (GSRS) prior 
to and after administration of galcanezumab or 
erenumab.
Change from baseline in GSRS after administration of 
galcanezumab or erenumab within each treatment group at 
Weeks 2 and 4.
To evaluate the Bristol stool form scale (BSFS)
prior to and after administration of galcanezumab or 
erenumab.
Change from baseline in BSFS after administration of 
galcanezumab or erenumab within each treatment group at 
Weeks 2 and 4.
Tertiary/Exploratory Objectives
To evaluate the transit time between galcanezumab 
and erenumab for

whole gut

gastric emptying

small bowel

colon

combined small and large bowel.
Change from baseline in transit time after administration 
of galcanezumab or erenumab between treatment groups at 
the end of Week 2 for

WGTT, in hours

GET, in hours

SBTT, in hours

CTT, in hours

combined SLBTT, in hours.
To evaluate number of weekly spontaneous bowel 
movements (un-aided by laxatives, enemas, or 
suppositories) prior to and after administration of 
galcanezumab or erenumab.
Change from baseline in number of weekly spontaneous 
bowel movements after administration of galcanezumab or 
erenumab between each treatment group at Weeks 2 and 4.


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Objectives
Endpoints
To evaluate GSRS prior to and after administration 
of galcanezumab or erenumab.
Mean change difference from baseline in GSRS scores
after administration of galcanezumab or erenumab
between treatment groups at Weeks 2 and 4 post-
treatment.
To evaluate the BSFS prior to and after 
administration of galcanezumab or erenumab.
Mean change difference from baseline in BSFS scores
after administration of galcanezumab or erenumab
between treatment groups at Weeks 2 and 4 post-
treatment.
Summary of Study Design:
Study CGBC is a multicenter, randomized, single-blind study with 2 study periods in patients 
with migraine deemed eligible for preventive treatment by the study physician. Within the 2 
study periods, there are a total of 5 onsite patient visits:
Visit
Description
Visit 1
Informed consent and screening
Visit 2
First WMC administration and lead-in
Visit 3
Randomization and dosing
Visit 4
Second WMC administration
Visit 5
Exit visit
Treatment Arms and Duration:
Two treatment arms: galcanezumab (240-mg loading dose) and erenumab 140 mg. 
At Visit 1, the study investigators will screen patients to determine their eligibility and 
administer study-specific questionnaires if the patients are deemed eligible . At Visit 2, 
administration of the WMC will occur.  At Visit 3, patients will be randomized 1:1 to receive 
single-blind galcanezumab (240-mg loading dose) or erenumab 140 mg, which will be 
administered by onsite study staff. At Visit 4, approximately 14 days following study treatment
administration (Visit 3), patients will be administered their second WMC upon return to site.  
Patients will return to the study site approximately 14 days following ingestion of the second
WMC for Visit 5 exit visit.
Number of Patients:
The study will screen an estimated 75 potential study participants to ensure randomization of 
approximately 60 eligible patients.
Statistical Analysis:
Unless otherwise specified, analyses 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 treatment.
Patients in the ITT population will be analyzed according to the treatment group to which they 
are randomized. When change from baseline is assessed, the patient will be included in the 
analysis only if the patient has baseline and postbaseline measurements.


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The primary analysis will evaluate the changes in CTT between pre- and post-drug 
administration within each treatment group.  The primary analysis will be performed using an 
analysis of covariance (ANCOVA) model. The analysis will include the categorical effects of 
treatment and all randomization stratification factors, as well as the continuous baseline CTT.
Least squares mean (LSMean) change from baseline in each treatment group will be tested to 
detect any change in CTT between pre- and post-drug administration.


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2. Schedule of Activities


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Table CGBC.2.1.
Schedule of Activities
Study Period
SP I
Screening and 
Baseline GI 
Transit Time
SP II
Single-Blind Treatment and Post 
WMC Evaluation
Notes
Visit
V1
V2
V3
V4
V5
Day
-8 ± 2
-7 ± 2
0
14 ± 3
28 ± 3
Patient education regarding WMC
X
Calibrate Medtronic WMC
X
X
WMC administration
Xa
X

Fasting is defined as no food or drink, except 
water, for at least 8 hours prior to testing.

No alcohol consumption for 24 hours prior to 
ingesting the WMC and 6 hours after ingestion.

Tobacco use should also be avoided for 8 hours 
before ingestion and 6 hours after ingestion of 
the WMC.

Patients will consume a SmartBar immediately 
before ingesting WMC and will fast for 6 hours 
following WMC ingestion.

Patients should not sleep for 6 hours after 
ingesting the WMC.
Assessment that WMC has been 
expelled
Xb
Xb
The recorder will be returned to the site and data will be 
uploaded and evaluated to confirm WMC expulsion at 
Visit 3 and between Visits 4 and 5.
Study treatment administered
X
Procedures
Informed consent
X
Inclusion and exclusion criteria
X
Concomitant medication review
X
X
X
X
X


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Study Period
SP I
Screening and 
Baseline GI 
Transit Time
SP II
Single-Blind Treatment and Post 
WMC Evaluation
Notes
Visit
V1
V2
V3
V4
V5
Urine pregnancy test, performed 
locally
X
X
Eligible patient randomized via 
IWRS
X
Physical examination
X
Height
X
Weight
X
Medical history
X
Substance use
X
X
X
Substances:  alcohol, caffeine, nicotine, tobacco.
Vital signs
X
X
X
X
Includes body temperature, sitting blood pressure, and 
pulse.
Assessment of migraine and 
headache days
X
Will be done retrospectively for the previous month.
GI Symptom Rating Scale (GSRS)
X
X
X
X
Bristol Stool Form Scale
X
X
X
X
Spontaneous Bowel movement 
(SBM) frequency evaluation
X
X
X
X
Adverse events
X
X
X
X
X
Abbreviations:  GI = gastrointestinal; IBS = irritable bowel syndrome; IWRS = interactive web-response system; SP = study period; TT = transit time; V = visit; 
WMC = wireless motility capsule.
a
If the patient meets the requirement of fasting at Visit 1, then Visit 1 and Visit 2 could be combined. Sites must not instruct patients to fast prior to signing the 
ICF
b
An x-ray may be obtained in the event that the expulsion of the WMC cannot be confirmed.


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3. Introduction
3.1.
Study Rationale
Differences have been observed between reported frequencies of constipation in clinical trials
and postmarketing adverse event (AE) reporting among calcitonin gene-related peptide (CGRP) 
antagonists. In particular, these differences have been observed between CGRP monoclonal 
antibodies (mAb) that target the ligand (galcanezumab, fremanezumab) or the receptor 
(erenumab) for the prevention of migraine (Stauffer et al. 2018b; Ashina et al. 2019; Robbins 
2019; Silberstein et al. 2019; Aimovig package insert, 2020).  Preclinical animal studies suggest 
that the different mechanisms of action of these agents may contribute to the different 
frequencies of constipation (Hargreaves and Olesen 2019). The purpose of Study I5Q-MC-
CGBC (CGBC) is to measure gastrointestinal (GI) transit time in adult patients with migraine
who have been initiated on preventive treatment with a CGRP antagonist (galcanezumab or 
erenumab), and explore whether there is a mechanistic difference that contributes to GI AEs in 
humans.
Medtronic’s wireless motility capsule (WMC) technology, which is commercially available, will 
be used to evaluate total GI transit time as well as segmental transit time. The Medtronic WMC
technology includes a WMC (SmartPill™Motility Capsule), a wearable data recorder 
(SmartPill™Motility Recorder), and a software program (MotiliGI™).  The system measures 
whole gut and regional (stomach, small bowel, and colon) transit time by measuring pressure, 
pH, and temperature throughout the GI tract (Medtronic 2017).  The US Food and Drug 
Administration has approved the system for the evaluation of adult patients with suspected 
delayed gastric emptying and the evaluation of colonic transit time (CTT) and combined small 
and large bowel transit time (SLBTT) in patients with chronic constipation (Saad and Hasler 
2011; Medtronic 2017).  The American and European Neurogastroenterology and Motility 
Societies recognized the WMC technology as a validated, standardized, objective measure of GI 
transit time and recommended its use for testing in individuals with suspected alterations of GI 
motility (Rao et al. 2011).  Patients’ baseline transit times will be measured with the WMC prior 
to first dose of the CGRP antagonist in patients with migraine deemed eligible by the study 
investigator. Two weeks following study treatment administration, a second WMC will be 
administered to obtain comparative transit time values to one’s baseline for those patients in each 
treatment group.
3.2.
Background
Recent publications have illustrated that CGRP can induce pharmacological effects at the CGRP 
receptor, as well as being a potent agonist at the amylin 1 (AMY1) receptor.  As such, an 
antibody that binds to the CGRP receptor (erenumab) will block the effects of CGRP at the 
CGRP receptor, but will not inhibit the effects of CGRP at the AMY1 receptor.  In contrast, an 
antibody that binds to CGRP itself (galcanezumab) will inhibit the pharmacological effects of 
CGRP at both the CGRP and AMY1 receptors (Figure CGBC.3.1).  Amylin is an agonist at the 
AMY1 receptor, but is a very weak activator of the CGRP receptor (Hay 2017; Hay et al. 2018; 


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Hargreaves and Olesen 2019).  The effects of amylin at the AMY1 receptor will persist in the 
presence of either antibody.
Calcitonin gene-related peptide receptors are located throughout the GI system of rodents and 
humans, including both the small and large intestines.  Calcitonin gene-related peptide infusion 
has been reported to cause GI symptoms in 93% of human subjects (Falkenberg and Olesen
2019).  Additionally, CGRP (administered intraperitoneally) has been shown to cause diarrhea in 
rodents that can be blocked by a CGRP antibody (Kaiser et al. 2017).  Investigators have 
reported constipation with treatment for migraine prevention in clinical trials of selective CGRP 
receptor antagonists that are higher (Ho et al. 2014; ClinicalTrials.gov 2018; Ashina et al. 2019; 
Aimovig package insert, 2020) than the CGRP antagonists at the ligand (Stauffer et al. 2018b; 
Silberstein et al. 2019).
Alternatively, activation of amylin receptors induces stasis of the GI system. Amylin receptors 
are found on nerves projecting to the GI tract.  The amylin analog, pramlintide, slows gastric 
emptying and is contraindicated in patients with gastroparesis.  An amylin antagonist (AC187) 
accelerates gastric emptying in rats.
One possible explanation for the differences between reported frequencies of constipation in
Phase 2 and 3 clinical trials, postmarketing clinician observation, and postmarketing AE
reporting for monoclonal antibodies that act at the CGRP ligand versus the CGRP receptor could 
involve the effects of CGRP at the AMY1 receptor (Hay et al. 2018; Stauffer et al. 2018b; 
Aimovig package insert, 2020; Ashina et al. 2019; Hargreaves and Olesen 2019; Robbins 2019; 
Silberstein et al. 2019).  By blocking the CGRP receptor, the CGRP receptor antagonist 
(erenumab) would decrease the motility-enhancing characteristics of CGRP while maintaining, 
or perhaps increasing, the GI motility-slowing effects via AMY1 receptor activation.  
Alternatively, the CGRP antagonist acting at the ligand would inhibit the motility-enhancing and 
motility-slowing effects of CGRP at the CGRP and AMY1 receptors, respectively, with the net 
effect being little to no change in GI transit time.  This hypothesis will be studied in this clinical 
trial.


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Abbreviations:  AMY1 = amylin 1; CGRP = calcitonin gene-related peptide.
Figure CGBC.3.1.
Mechanism of action of CGRP monoclonal antibodies.
3.3.
Benefit/Risk Assessment
Galcanezumab is a humanized monoclonal antibody that potently and selectively binds to CGRP 
and prevents its biological activity without blocking the CGRP receptor.  The efficacy of 
galcanezumab in the prevention of migraine has been demonstrated in three Phase 3 randomized, 
double-blind, placebo-controlled trials, which found statistically significant and clinically 
meaningful mean reduction of monthly migraine headache days and improvement in patient 
function compared with placebo in patients with episodic and chronic migraine (Detke et al. 
2018; Skljarevski et al. 2018; Stauffer et al. 2018a).  Across Phase 2 and Phase 3 clinical studies 
in patients with migraine, galcanezumab exhibited a favorable safety profile at doses up to 300 
mg every 4 weeks for 3 months, or 240 mg monthly for up to 1 year (Camporeale et al. 2018; 
Dodick et al. 2014; Oakes et al. 2018; Skljarevski et al. 2018; Stauffer et al. 2018a).  The 
incidences of serious adverse events (SAEs) and discontinuations due to AEs were low, and 
treatment-emergent adverse events (TEAEs) were generally of mild to moderate severity.  In the 
Phase 3 studies, the most commonly reported TEAEs were injection site pain and injection site 
reactions, also generally of mild to moderate severity.  There was no evidence of an effect on 
cardiovascular function.  Additionally, in postmarketing experience, hypersensitivity reactions, 
including anaphylaxis, angioedema, dyspnea, urticaria, and rash, have been reported with 
galcanezumab.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated AEs of galcanezumab are to be found in the Investigator’s Brochure (IB).


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Erenumab is a human monoclonal antibody that antagonizes the CGRP receptor.  The efficacy of 
erenumab for the prevention of migraine has been demonstrated in three Phase 3 randomized, 
double-blind trials (Goadsby et al. 2017; Tepper et al. 2017; Dodick et al. 2018).  Erenumab 70 
and 140 mg were both found to be effective in reducing the number of monthly migraine days in 
patients with episodic and chronic migraine.  No serious safety concerns were identified with a 
clear causal relationship to erenumab.  The incidences of SAEs and discontinuations due to AEs 
were low, and the most common adverse reactions (with an incidence of at least 2% for either 
dose of erenumab and at least 2% greater than placebo) were injection site reactions,
constipation, and cramps/muscle spasms (Ashina et al. 2019; Aimovig package insert, 2020).
Hypersensitivity reactions (including rash, angioedema, and anaphylaxis), constipation with 
serious complications, and new-onset or worsening of pre-existing hypertension have been 
reported with erenumab in postmarketing experience.
The risks of WMC include capsule retention and aspiration, which rarely and very rarely are 
reported.  With regard to the cases of capsule retention, they resolved either without intervention 
or with endoscopy/colonoscopy. Surgery was required for resolution in one instance of capsule 
small bowel retention that led to identification of a stricture. 
To minimize these risks, patients with a history of GI surgery, a self-reported history of gastric 
bezoars, swallowing disorders, severe dysphagia to food or pills, suspected or known strictures, 
fistulas, or physiological/mechanical GI obstruction are excluded to participate in the study.
Patients should not undergo a magnetic resonance imaging (MRI) test until capsule passage is 
confirmed by review of the MotiliGI™graph or x-ray of kidneys, ureter, and bladder. If a WMC
is in the body during an MRI test, there is a risk of damage to the GI tract.


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galcanezumab (LY2951742)
4.
Objectives and Endpoints
Table CGBC.4.1 shows the objectives and endpoints of the study.
Table CGBC.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary Objective
To evaluate colonic transit time (CTT) in patients 
with migraine 1 week prior to and 2 weeks after
administration of an initial loading dose of 
galcanezumab 240 mg or erenumab 140 mg.
Change from baseline in CTT after administration of 
galcanezumab or erenumab within each treatment group in 
hours at the end of Week 2.
Secondary Objectives
To evaluate transit time of the following segments 
of the gastrointestinal (GI) tract 1 week prior to and 
2 weeks after administration of galcanezumab or 
erenumab:

whole gut

gastric emptying

small bowel

combined small and large bowel.
Change from baseline in GI transit time in each of the 
following segments after administration of galcanezumab 
or erenumab within each treatment group at the end of 
Week 2:

Whole gut transit time (WGTT), in hours

Gastric emptying time (GET), in hours

Small bowel transit time (SBTT), in hours

Combined small and large bowel transit time 
(SLBTT), in hours.
To evaluate the frequency of contractions, motility 
index, and area under the pressure curve (AUC) by 
quartile in the colon to assess for correlation with 
CTT results.
Changes in pressure parameters from baseline:

Contraction Freq/Min

Motility Index =  ln (# of contractions x 
∑pressure amplitudes +1)  

Area under the Pressure Curve.
To evaluate number of weekly spontaneous bowel 
movements (un-aided by laxatives, enemas, or 
suppositories) prior to and after administration of 
galcanezumab or erenumab.
Change from baseline in number of weekly spontaneous 
bowel movements after administration of galcanezumab or 
erenumab within each treatment group at Weeks 2 and 4.
To evaluate GI symptom rating scale (GSRS) prior 
to and after administration of galcanezumab or 
erenumab.
Change from baseline in GSRS after administration of 
galcanezumab or erenumab within each treatment group at 
Weeks 2 and 4.
To evaluate the Bristol stool form scale (BSFS)
prior to and after administration of galcanezumab or 
erenumab.
Change from baseline in BSFS after administration of 
galcanezumab or erenumab within each treatment group at 
Weeks 2 and 4.
Tertiary/Exploratory Objectives
To evaluate the transit time between galcanezumab 
and erenumab for

whole gut

gastric emptying

small bowel

colon

combined small and large bowel.
Change from baseline in transit time after administration 
of galcanezumab or erenumab between treatment groups at 
the end of Week 2 for

WGTT, in hours

GET, in hours

SBTT, in hours 

CTT, in hours

combined SLBTT, in hours.
To evaluate number of weekly spontaneous bowel 
movements (un-aided by laxatives, enemas, or 
suppositories) prior to and after administration of 
galcanezumab or erenumab. 
Change from baseline in number of weekly spontaneous 
bowel movements after administration of galcanezumab or 
erenumab between each treatment group at Weeks 2 and 4.


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galcanezumab (LY2951742)
Objectives
Endpoints
To evaluate GSRS prior to and after administration 
of galcanezumab or erenumab.
Mean change difference from baseline in GSRS scores 
after administration of galcanezumab or erenumab 
between treatment groups at Weeks 2 and 4 post-
treatment.
To evaluate the BSFS prior to and after 
administration of galcanezumab or erenumab.
Mean change difference from baseline in BSFS scores 
after administration of galcanezumab or erenumab 
between treatment groups at Weeks 2 and 4 post-
treatment.


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5. Study Design
5.1.
Overall Design
Study CGBC is a multicenter, randomized, single-blind, Phase 4 study with 2 study periods in 
patients with migraine who are deemed eligible for preventive treatment by the study 
investigator.  The study has 2 periods: a screening period to determine patient eligibility and 
lead-in with a baseline WMC test; and an single-blind treatment period with a post-study 
treatment WMC test.
Study governance considerations are described in detail in Appendix 2.
Figure CGBC.5.1 illustrates the study design.
Abbreviations:  LD = loading dose; Single-Blind = only the investigator, site personnel,
and sponsor will know the randomized treatment after randomization; SP = study 
period; WMC = wireless motility capsule.
Figure CGBC.5.1.
Illustration of study design for Clinical Protocol I5Q-MC-CGBC.
Study Period I:  The study and potential risks will be explained to the patient at Visit 1.  The 
informed consent form (ICF) must be signed before any study procedures are performed.
The screening and baseline GI transit time visit (Visit 1) will consist of a full clinical assessment, 
including a comprehensive medical evaluation documenting medical history, and a physical 
examination (see Schedule of Activities, Section 2) to confirm eligibility.  Visit 2 includes 
administration of the WMC and receipt of recorder to patients meeting all eligibility 
requirements.


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Study Period II:  At the start of the single-blind treatment period (Visit 3), patients will be 
randomized in a 1:1 ratio to receive galcanezumab 240 mg loading dose or erenumab 140 mg.  
Patients will be administered 2 galcanezumab injections of 120 mg each to achieve the 240-mg 
loading dose or 2 erenumab injections of 70 mg each to achieve the 140-mg dose.  At Visit 4, an 
additional WMC and recorder will be given to patients following calibration.  Patients will exit 
the study at Visit 5.
5.2.
Number of Participants
The study will screen an estimated 75 potential study participants to ensure randomization of 
approximately 60 patients with migraine.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
Refer to Section 3.1 for further information.
5.5.
Justification for Dose
A galcanezumab 240-mg loading dose (2 consecutive injections of 120 mg each) or a dose of 
140 mg erenumab (2 consecutive injections of 70 mg each) will be administered by subcutaneous 
injection because both galcanezumab and erenumab have been approved in the US at these 
respective doses for migraine prevention.


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet all of the following criteria at 
screening:
Patient and Disease Characteristics
[1]
Patients are 18 to 55 years of age (inclusive) at the time of screening.
[2]
Have a diagnosis of migraine (1.1 and 1.2 ICHD), with or without aura, as 
determined by the study investigator and in consideration of International 
Headache Society International Classification of Headache Disorders – 3rd 
edition guidelines (ICHD-3 2018).
[3]
Have a frequency of less than 15 monthly headache days of which up to 14 
can be migraine headache days.
[4]
Patients can be on no more than 1 other migraine preventive treatment (except 
for tricyclic antidepressants and verapamil) as long as:

that patient has had a stable dose of the oral migraine preventive treatment for a 
minimum of 2 months
or

patients that have received onabotulinumtoxinA for a minimum of 2 cycles prior 
to Visit 1.
Informed Consent and Patient Agreements
[5]
Are able and willing to give signed informed consent.
[6]
Are reliable and willing to follow study procedures.
[7]
Male patients must agree to use a reliable method of birth control during the 
study as well as for 5 months after dosing with study treatment.
[8]
Women of childbearing potential must test negative for pregnancy at the time 
of enrollment based on a urine pregnancy test.
[9]
Women of childbearing potential who are abstinent from sexual intercourse 
must agree to remain abstinent during the study as well as for 5 months after 
dosing with study treatment.


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[10] Otherwise, women of childbearing potential must agree to use 1 highly 
effective method of contraception (including a male partner who has had a 
vasectomy), or a combination of 2 effective methods of contraception during 
the study as well as for 5 months after dosing with study treatment. Birth 
control is not required if the female is infertile due to surgical sterilization 
(hysterectomy, or at least 6 weeks after surgical bilateral oophorectomy or 
tubal ligation) confirmed by medical history or menopause.
[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 (e.g., 
Facebook, Twitter, LinkedIn, Google+, etc.) until the entire trial has 
completed.
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at 
screening:
Medical Conditions
[12] Prior to Visit 1, less than 3 bowel movements in the previous 7 days.
[13] Patients with a history of irritable bowel syndrome (IBS) or chronic 
constipation.
[14] Patients with a self-reported history of gastric bezoars, swallowing disorders, 
severe dysphagia to food or pills, suspected or known strictures, fistulas, or 
physiological/mechanical GI obstruction.
[15] History of GI surgery with the exception of cholecystectomy, appendectomy,
or Nissen fundoplication.
[16] History of any abdominal surgery within the past 3 months.
[17] History of bariatric surgery.
[18] History of Crohn’s disease, celiac disease, ulcerative colitis, or diverticulitis.
[19] Patients with type 1 or type 2 diabetes.
[20] Patients with cardiac pacemakers or other implanted or portable 
electromechanical device.
[21] Patients with a body mass index (BMI) of ≥40 kg/m2.
[22] Women who are pregnant or nursing.
[23] History of drug or alcohol abuse/dependence within 1 year prior to Visit 1 
(excessive or compulsive use as judged by the investigator), or currently using 
drugs of abuse (including opioids, barbiturates, and marijuana), or any 
prescribed or over-the-counter medication in a manner that the investigator 
considers indicative of abuse/dependence.


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[24] Have an acute, serious, or unstable medical condition that, in the judgment of 
the investigator, indicates a medical problem that would preclude study 
participation.
[25] Myocardial infarction, unstable angina, percutaneous coronary intervention, 
coronary artery bypass graft, stroke, deep vein thrombosis, or pulmonary 
embolism within 6 months of screening, or have planned cardiovascular 
surgery or percutaneous coronary angioplasty.
[26] Patients who, in the clinician’s judgment, are actively suicidal and therefore 
deemed to be at significant risk for suicide, or have had clinically significant 
suicidal ideation within the past month (e.g., includes some plan or intent to 
act), or have had any suicidal behavior within the past month.
Prior/Concomitant Therapy
[27] Patients currently receiving a mAb CGRP antagonist or have received a mAb
CGRP antagonist within the past 6 months prior to Visit 1.
[28] Have received an oral CGRP antagonist (gepant) 14 days prior to Visit 1.
[29] Known hypersensitivity to monoclonal antibodies or other therapeutic 
proteins, or to galcanezumab.
[30] Known allergy to SmartBar ingredients including granola (rolled oats, 
evaporated cane juice, expeller pressed canola oil, defatted wheat germ, oat 
flour, brown rice syrup, molasses, salt, natural flavor, soy lecithin), whey 
crisp, rice syrup, corn syrup, whey protein isolate, invert sugar, puffed wheat, 
apples, maltodextrin, sorbitol, apple juice concentrate, partially hydrogenated 
vegetable oil (cottonseed, soybean), honey, natural and artificial flavor, salt, 
gluten, vanilla.
[31] Medications known to alter GI transit times including opioids, tricylic 
antidepressants, verapamil, and medications that can affect the WMC test such 
as proton pump inhibitors, are excluded from the study 1 week prior to Visit 2 
and at any time after Visit 2.  See medication exclusion list for a full list of 
excluded medications.
Prior/Concurrent Clinical Trial Experience
[32] Are currently enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
Other Exclusions
[33] In the opinion of the investigator, have other issues that would interfere with 
compliance with the study requirements and completion of evaluations 
required for this study.


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[34] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[35] Are Lilly employees or are employees of Medtronic.
[36] Are unwilling or unable to comply with the use of a data collection device to 
directly record data from the subject.
6.3.
Lifestyle Restrictions
No vigorous exercise, such as sit-ups, abdominal crunches, or prolonged extreme exercises,
should be performed throughout the duration of the WMC test, which is approximately 5 days.
Patients should maintain consistent dietary habits throughout the duration of the study (from 
Visit 1 to Visit 5).
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be
considered for rescreen once, with approval from Lilly Medical for only the criteria shown 
below.  The interval between screening and rescreening must be at least 45 days or longer if 
required for the specified time frames 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.

Inclusion criterion 1:  If patients are less than 18 years old at the time of informed 
consent, they may be rescreened when they reach 18 years of age during the study 
enrollment period.

Exclusion criterion 27, 28, and 31:  Patients using a concomitant medication that 
requires a stable dose for a specific duration prior to Visit 1 may be rescreened if 
additional time is needed to meet the duration requirement.


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7. Treatments
7.1.
Treatments Administered
This study involves an evaluation of GI transit time in patients who receive galcanezumab 
240 mg administered by subcutaneous injection and erenumab 140 mg administered by 
subcutaneous injection. Both galcanezumab and erenumab will be administered by site staff 
once with an autoinjector (AI) pen at Visit 3 of the study.  Table CGBC.7.1 shows the treatment 
regimens.
Table CGBC.7.1.
Treatment Regimens
Regimen
Dose
Day 7 ± 2
Galcanezumab 240 mg
240 mg
(2 120-mg SC injection)
Erenumab 140 mg
140 mg
(2 70-mg SC injection)
Abbreviation:  SC = subcutaneous.
The investigator or his/her designee is responsible for

verifying that instructions are followed properly

maintaining accurate records of study treatment dispensing and collection, and

at the end of the study, returning all unused medication to Lilly, or its designee, 
unless the sponsor and sites have agreed that all unused medications are to be 
destroyed by the site, as allowed by local law.
7.1.1. Packaging and Labeling
Galcanezumab and erenumab will be supplied as an injectable solution in 1-mL, single-dose, 
prefilled, disposable AI pen. Each AI pen of galcanezumab is designed to deliver 120 mg/mL, 
and each AI pen of erenumab is designed to deliver 70 mg/mL. All AI pens will be supplied in 
single pen cartons, with the site to select the appropriate quantity of AI pens, specific to the 
planned treatment schedule. Two galcanezumab AI pens are needed for the galcanezumab (240 
mg) treatment.  Two erenumab AI pens are needed for the erenumab (140 mg) treatment.
The commercial products being provided will be labeled with a commercially approved product 
label.  Each commercial product package is to have a “For CT use only” label.
7.1.2. Medical Devices
The commercial medical devices provided for use in the study are AI pens and the SmartPill™ 
system.  The SmartPill™ motility testing system includes the SmartPill™ motility capsule
(WMC), the MotiliGI™ software, and the SmartPill™ motility recorder.


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7.2.
Method of Treatment Assignment
Patients who meet all criteria for enrollment will be randomized to single-blind treatment at 
Visit 3.  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system (IWRS).
To achieve between-group comparability, the randomization will be stratified by site, BMI 
category (<30 kg/m2, ≥30 kg/m2), and by baseline migraine frequency (<8 migraine headache 
days versus ≥8 migraine headache days).
7.2.1. Selection and Timing of Doses
The study treatment will be administered only once at Visit 3.
7.3.
Blinding
This is a single-blind study. Only the investigator, site personnel, and sponsor will know the 
randomized treatment after randomization. Site Personnel are responsible to ensure patients 
remain blinded to treatment (i.e., patients must not see the AI pens before, during, or after the 
drug administration). See the Manual of Operations for further details regarding blinding.
7.4.
Dosage Modification
Not applicable.
7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

confirming appropriate temperature conditions have been maintained during 
transit for all study treatment received and any discrepancies are reported and 
resolved before use of the study treatment.

ensuring that only participants enrolled in the study may receive study treatment 
and only authorized site staff may supply or administer study treatment. All study 
treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions 
with access limited to the investigator and authorized site staff.

the investigator, institution, or the head of the medical institution (where 
applicable) is responsible for study treatment accountability, reconciliation, and 
record maintenance (such as receipt, reconciliation, and final disposition records).
The study treatment must be stored according to the storage requirements printed onto the 
commercial label.
To administer the galcanezumab or erenumab injections, the investigational sites are to refer to 
the commercial package insert for the preparation and handling instructions of each study 
treatment.


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7.6.
Treatment Compliance
Patient compliance with study medication will be assessed at the dosing visit.  Deviation(s) from 
the prescribed dosage regimen should be recorded in the electronic case report form (eCRF).
7.7.
Concomitant Therapy
The list of excluded medications and procedures is provided in the Manual of Operations.  Any 
changes in the list of allowed/not allowed medications will be communicated to investigators and 
will not constitute a protocol amendment.
7.8.
Treatment after the End of the Study
Study treatment will not be made available to patients after conclusion of the study.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of study treatment:

Subject Decision
o
the patient requests to discontinue study treatment.

In addition, patients will be discontinued from the study treatment in the following 
circumstances:
o
WMC retention or aspiration
Patients discontinuing from the study prematurely for any reason should complete AE and other 
follow-up procedures per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
8.1.2. Temporary Discontinuation from Study Treatment
Not applicable.
8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identifies a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue study 
treatment.  If the investigator and the sponsor clinical research physician (CRP)/clinical research 
scientist (CRS) agree it is medically appropriate to continue, the investigator must obtain 
documented approval from the sponsor CRP/CRS to allow the inadvertently enrolled patient to 
continue in the study with or without study treatment. Safety follow-up is as outlined in Section 
2 (Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the 
protocol.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:

enrollment in any other clinical study involving an study treatment or 
enrollment in any other type of medical research judged not to be 
scientifically or medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and Good 
Clinical Practice (GCP)

investigator decision


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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 that has been demonstrated to be effective for treatment of the study 
indication, discontinuation from the study occurs prior to introduction of 
the new agent

patient decision
o
the patient requests to be withdrawn from the study

patient becomes pregnant.
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-Up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the patient 
within legal and ethical boundaries for all patients randomized, including those who did not 
receive study treatment.  Public sources may be searched for vital status information.  If vital 
status is determined, this will be documented and the patient will not be considered lost to 
follow-up.
Lilly personnel will not be involved in any attempts to collect vital status information.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
9.1.
Efficacy Assessments
9.1.1. Primary Assessment of GI Transit Time
The WMC (Medtronic 2017) measures whole gut and regional gut (stomach, small bowel, and 
colon) transit times through measurement of pH, pressure, and temperature throughout the GI 
tract.  Once enrolled into study, the patient will be asked to eat a SmartBar, followed by 
ingesting the WMC with 120 mL of water.  The patient will then be instructed to fast for an 
additional 6 hours after the WMC is administered and wear an external data recorder for up to 5 
days. The WMC is a 4.5-g indigestible single-use, 27 12 mm cylindrical capsule.  Data are
transferred to the accompanied wearable external data recorder and displayed and analyzed using 
MotiliGI™version 3.1 software (Medtronic 2017).
The baseline and postbaseline WMC test will be assessed by expert readers who are blind to 
treatment assignment.
9.1.2. Secondary Assessment Scales
Gastrointestinal Symptom Rating Scale.  The Gastrointestinal Symptom Rating Scale (GSRS) 
is a validated 15-item questionnaire that evaluates the 5 common symptoms of GI disorders: 
abdominal pain, reflux, indigestion, constipation, and diarrhea. Items ask about the past week 
using a 7-point categorical response scale from no discomfort to very severe discomfort (Revicki 
et.al 1998; Khanna 2017).
Bristol Stool Form Scale. The Bristol Stool Form Scale (BSFS) is a 7-point ordinal scale of 
stool types ranging from the hardest (Type 1) to the softest (Type 7). Symptoms of constipation 
are related to harder stools (Types 1 and 2) and symptoms of diarrhea are related to loose/liquid 
stools (Types 6 and 7). Overall, stool Type 3 to 5 are considered normal.  BSFS provides the 
patient with a pictorial representation of each type of stool (Blake et al. 2016).
9.1.3. Appropriateness of Assessments
The efficacy and safety assessments used in this study have been well documented and are 
generally regarded as reliable, accurate, and are relevant for use in this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.


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The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the study treatment
or the study, or that caused the patient to discontinue the study treatment before completing the 
study.  The patient should be followed up until the event resolves, stabilizes with appropriate 
diagnostic evaluation, or is reasonably explained.  The frequency of follow-up evaluations of the 
AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
The investigator will record all relevant AE and SAE information in the eCRF.  After the ICF is 
signed, study site personnel will record via eCRF the occurrence and nature of each patient’s 
preexisting conditions, including clinically significant signs and symptoms of the disease under 
treatment in the study.  In addition, site personnel will record any change in the condition(s) and 
any new conditions as AEs. Investigators should record their assessment of the potential 
relatedness of each AE to protocol procedure and study treatment, via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause-and-effect relationship between the study 
treatment, study device, and/or study procedure and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s study treatment is discontinued as a result of an AE, study site personnel must 
report this to Lilly or its designee via eCRF, clarifying if possible the circumstances leading to 
any dosage modifications, or discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e., immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect


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
important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition.  Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.

when a condition related to the AI pen necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or 
permanent damage to a body structure, the serious outcome of “required 
intervention” will be assigned.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The SAE reporting to the sponsor begins after the patient has signed the ICF and has 
received study treatment.  However, if an SAE occurs after signing the ICF, but prior to 
receiving study treatment, the SAE should be reported to the sponsor as per SAE reporting 
requirements and timelines (see Section 9.2) if it is considered reasonably possibly related to 
study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed by official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.
Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE.  However, to fulfill regulatory requirements any pregnancy should be reported 
following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient disposition eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the galcanezumab IB or the erenumab US package insert (USPI) and that the investigator 
identifies as related to study treatment or procedure.  United States 21 CFR 312.32 and European 
Union Clinical Trial Directive 2001/20/EC and the associated detailed guidances or national 
regulatory requirements in participating countries require the reporting of SUSARs.  Lilly has 
procedures that will be followed for the identification, recording, and expedited reporting of 
SUSARs that are consistent with global regulations and the associated detailed guidances.


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9.2.2. Complaint Handling
Lilly collects product complaints on study treatment and drug delivery systems used in clinical 
studies to ensure the safety of study participants, monitor quality, and to facilitate process and 
product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the study treatment (galcanezumab or erenumab) or device (AI or 
WMC) so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB for galcanezumab and the Product Label for erenumab.
9.4.
Safety
9.4.1. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via eCRF.
9.4.2. Laboratory Tests
For each patient, the local urine pregnancy test should be conducted according to the Schedule of 
Activities (Section 2).
9.4.3. Immunogenicity Assessments
Not applicable.
9.4.4. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
9.4.4.1.
Hepatic Safety Monitoring
Not applicable.
9.5.
Pharmacokinetics
Not applicable.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Genetics
Not applicable.


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9.8.
Biomarkers
Not applicable.
9.9.
Health Economics
Health Economics and Medical Resource Utilization parameters are not evaluated in this study.


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10. Statistical Considerations
10.1. Sample Size Determination
Assuming within-group mean difference in CTT is about 4.2 hours with standard deviation of 
approximately 8, a sample of 30 patients in each treatment group will provide 80% power to 
detect the difference within the treatment group.  The total sample size for the study would be 
60.
Assuming 20% screen failure rate, approximately 75 patients may be screened to enroll 60
patients into the study. Eligible patients will be randomized in a 1:1 ratio to galcanezumab or 
erenumab to have about 30 patients in each treatment group.
10.2. Populations for Analyses
For purposes of analysis, the intent-to-treat (ITT) population will be used. The ITT population 
includes all patients who are randomized and received study treatment. Other populations may 
be explored if appropriate, such as the ITT population excluding patients taking prohibited 
medications that are known to have an effect on GI motility or the WMC test. 
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee. Details of 
statistical analysis methods will be described in the statistical analysis plan (SAP).
Unless otherwise specified, analyses will be conducted on the ITT population, which will include 
all patients who are randomized and receive at least 1 dose of study treatment. Patients in the 
ITT population will be analyzed according to the treatment group to which they are randomized. 
When change from baseline is assessed, the patient will be included in the analysis only if the 
patient has baseline and postbaseline measurements.
Investigative sites with fewer than 4 randomized patients per treatment group will be pooled for 
statistical analysis purposes.
All tests of within-group and between-group comparisons will be conducted at a 2-sided alpha 
level of 0.05, unless otherwise stated.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the SAP or the clinical study report (CSR).  Additional exploratory analyses of the data will be 
conducted as deemed appropriate.


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10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
The number and percentage of ITT patients who complete the study or discontinue early will be 
summarized for both treatment groups. A detailed description of patient disposition will be 
provided at the end of the study.
Patient allocation by investigative site will be summarized for ITT population. Patient allocation 
by investigative site will also be listed.
10.3.2.2. Patient Characteristics
The following patient characteristics at baseline will be summarized by treatment group for ITT 
population:

demographics (age, gender, ethnic origin, height, weight, body mass index)

medical history and pre-existing condition

total gut and segmental transit times, and

GI symptom rating scale, SBM frequency, and Bristol stool form scale.
10.3.2.3. Concomitant Therapy
The proportion of patients who received concomitant medication will be summarized for all ITT 
patients.
10.3.2.4. Treatment Compliance
Not applicable.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary objective is to assess changes in CTT between pre- and post-drug administration 
within each treatment group.  The primary measure is the mean change from baseline in the CTT
2 weeks after drug administration within each treatment group.
The primary analysis will be performed using an analysis of covariance (ANCOVA) model.  The 
analysis will include the categorical effects of treatment and all randomization stratification 
factors (site, baseline migraine frequency, and BMI category; see Section 7.2), as well as the 
continuous baseline CTT. Least squares mean change from baseline in each treatment group will 
be tested to detect any change in CTT between pre- and post-drug administration.
10.3.3.2. Secondary Analyses
For continuous secondary measures with single postbaseline measurement, analysis will be 
performed using an ANCOVA model. The analysis will include the categorical effects of 
treatment and all randomization stratification factors, as well as the continuous baseline value.
Least squares mean change from baseline in each treatment group will be tested to detect any 
changes between pre- and post-drug administration. Least squares mean change from baseline in 
2 treatment groups will be compared to detect any between-group differences.


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10.3.3.3. Tertiary/Exploratory Analyses
For continuous measures with repeated postbaseline measurements, change from baseline will be 
analyzed using a restricted maximum likelihood-based mixed effects model for repeated 
measures technique (MMRM).  The analysis will include the fixed categorical effects of 
treatment, all randomization stratification factors, investigative site, week, and 
treatment-by-week interaction, as well as the continuous fixed covariates of baseline value and 
baseline-by-week interaction. Details of MMRM model are described in the SAP, and further 
details regarding tertiary analyses are summarized in the SAP.
10.3.4. Safety Analyses
The safety analyses will be conducted for the single-blind treatment phase.
Safety data will be summarized by treatment group.
The safety and tolerability of treatment will be assessed by summarizing adverse events:

TEAEs
o
by Preferred Term (PT)
o
by System Organ Class (SOC)
o
by maximum severity
o
considered to be related to study treatment by investigator

SAEs, and

AEs leading to discontinuation.
Treatment-emergent adverse events are defined as the reported AEs that first occurred or 
worsened during the postbaseline 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 will 
be used in the treatment-emergent computation.  For each Lowest Level Term, 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 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 Lowest Level Terms 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.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
Not applicable.


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10.3.6. Evaluation of Immunogenicity
Not applicable.
10.3.7. Other Analyses
Not applicable.
10.3.7.1. Health Economics
Not applicable.
10.3.7.2. Subgroup Analyses
Not applicable.
10.3.8. Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the appropriate Lilly medical director, or designee, will be consulted to determine
whether it is necessary to amend the protocol.


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11.
References
Aamodt AH, Stovner LJ, Hagen K, Zwart JA. Comorbidity of headache and gastrointestinal 
complaints. The Head-HUNT Study. Cephalalgia. 2008;28(2):144-51.
Aimovig [United States Package Insert]. Thousand Oaks, CA: Amgen Inc.; 2020.
Ashina M, Kudrow D, Reuter U, Dolezil D, Silberstein S, Tepper SJ, Xue F, Picard H, Zhang F, 
Wang A, Zhou Y, Hong F, Klatt J, Mikol DD. Long-term tolerability and nonvascular safety 
of erenumab, a novel calcitonin gene-related peptide receptor antagonist for prevention of 
migraine: A pooled analysis of four placebo-controlled trials with long-term extensions 
[published online ahead of print 10 November 2019]. Cephalalgia. 
doi:10.1177/0333102419888222.
Blake MR, Raker JM, Whelan K. Validity and reliability of the Bristol Stool Form Scale in 
healthy adults and patients with diarrhoea‐predominant irritable bowel syndrome. Aliment 
Pharmacol Ther. 2016;44(7):693-703.
Camporeale A, Kudrow D, Sides R, Wang S, Van Dycke A, Selzler KJ, Stauffer VL. A phase 3, 
long-term, open-label safety study of Galcanezumab in patients with migraine. BMC Neurol
2018;18(1):188.
ClinicalTrials.gov. Efficacy, safety, and tolerability of multiple dosing regimens of oral 
atogepant (AGN-241689) in episodic migraine prevention. Available at: 
https://www.clinicaltrials.gov/ct2/show/results/NCT02848326?cond=atogepant&rank=5&vie
w=results. Accessed October 1, 2019.
Detke HC, Goadsby PJ, Wang S, Friedman DI, Selzler KJ, Aurora SK. Galcanezumab in chronic 
migraine: the randomized, double-blind, placebo-controlled REGAIN study. Neurology. 
2018;91(24):e2211-e2221.
Dodick DW, Ashina M, Brandes JL, Kudrow D, Lanteri-Minet M, Osipova V, Palmer K, Picard 
H, Mikol DD, Lenz RA. ARISE: a phase 3 randomized trial of erenumab for episodic 
migraine. Cephalalgia. 2018;38(6):1026-1037.
Dodick DW, Goadsby PJ, Spierings EL, 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.
Falkenberg K, Olesen J. Two hour CGRP infusion causes gastrointestinal hyperactivity. 
Cephalalgia. 2019;39(suppl 1):191. Abstract IHC-PO-129.
FDA. FDA Adverse Events Reporting System (FAERS) Public Dashboard. Available at 
https://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4-0135608ddc13/sheet/7a47a261-d58b-
4203-a8aa-6d3021737452/state/analysis. Accessed October 31, 2019.
Goadsby PJ, Reuter U, Hallström Y, Broessner G, Bonner JH, Zhang F, Sapra S, Picard H, 
Mikol DD, Lenz RA. A controlled trial of erenumab for episodic migraine. N Engl J Med. 
2017;377(22):2123-2132.


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[ICHD-3] Headache Classification Committee of the International Headache Society (IHS). The 
International Classification of Headache Disorders, 3rd edition. Cephalalgia. 
2018;38(1):1-211.
Hargreaves R, Olesen J. Calcitonin gene‐related peptide modulators–the history and renaissance 
of a new migraine drug class. Headache. 2019;59(6):951-970.
Hay DL. Amylin. Headache. 2017;57(suppl 2):89-96.
Hay DL, Garelja ML, Poyner DR, Walker CS. Update on the pharmacology of calcitonin/CGRP 
family of peptides: IUPHAR Review 25. Br J Pharmacol. 2018;175(1):3-17.
Ho TW, Connor KM, Zhang Y, Pearlman E, Koppenhaver J, Fan X, Lines C, Edvinsson L, 
Goadsby PJ, Michelson D. Randomized controlled trial of the CGRP receptor antagonist 
telcagepant for migraine prevention. Neurol. 2014;83(11):958-966.
Kaiser EA, Rea BJ, Kuburas A, Kovacevich BR, Garcia-Martinez LF, Recober A, Russo AF. 
Anti-CGRP antibodies block CGRP-induced diarrhea in mice. Neuropeptides. 2017;64:95-99.
Khanna D, Hays RD, Shreiner AB, Melmed GY, Chang L, Khanna PP, Bolus R, Whitman C, 
Paz SH, Hays T, Reise SP. Responsiveness to change and minimally important differences of 
the patient-reported outcomes measurement information system gastrointestinal symptoms 
scales. Dig Dis Sci. 2017;62(5):1186-1192.
Medtronic. SmartPill™GI Monitoring System: User Manual SmartPill™ Software v3.1. 
Minneapolis, MN; 2017.
Oakes TM, Skljarevski V, Zhang Q, Kielbasa W, Hodsdon ME, Detke HC, Camporeale A, Saper 
JR. Safety of galcanezumab in patients with episodic migraine: a randomized 
placebo-controlled dose-ranging phase 2b study. Cephalalgia. 2018;38(6):1015-1025.
Rao SS, Camilleri M, Hasler WL, Maurer AH, Parkman HP, Saad R, Scott MS, Simren M, 
Soffer E, Szarka L. Evaluation of gastrointestinal transit in clinical practice: position paper of 
the American and European Neurogastroenterology and Motility Societies. 
Neurogastroenterol Motil. 2011;23(1):8-23.
Revicki DA, Wood M, Wiklund I, Crawley J. Reliability and validity of the Gastrointestinal 
Symptom Rating Scale in patients with gastroesophageal reflux disease. Qual Life Res. 
1998;7(1):75-83.
Robbins L. Erenumab side effects. Headache. 2019;59(7):1088-1089.
Saad RJ, Hasler WL. A technical review and clinical assessment of the wireless motility capsule. 
Gastroenterol Hepatol. 2011;7(12):795.
Silberstein SD, McAllister P, Ning X, Faulhaber N, Lang N, Yeung P, Schiemann J, Aycardi E, 
Cohen JM, Janka L, Yang R. Safety and tolerability of fremanezumab for the prevention of 
migraine: a pooled analysis of phases 2b and 3 clinical trials. Headache. 2019;59(6):880-890.
Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim BK, Yang JY. Efficacy and safety of 
galcanezumab for the prevention of episodic migraine: results of the EVOLVE-2 phase 3 
randomized controlled clinical trial. Cephalalgia. 2018;38(8):1442-1454.


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Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. Evaluation of 
galcanezumab for the prevention of episodic migraine: the EVOLVE-1 randomized clinical 
trial. JAMA Neurol. 2018a;75(9):1080-1088.
Stauffer VL, Wang S, Bangs ME, Oakes T, Carter J, Aurora SK. Safety data from phase 3 
clinical studies comparing galcanezumab and placebo in patients with episodic and chronic 
migraine. J Headache Pain. 2018b;19(suppl 1):77.
Tepper S, Ashina M, Reuter U, Brandes JL, Doležil D, Silberstein S, Winner P, Leonardi D, 
Mikol D, Lenz R. Safety and efficacy of erenumab for preventive treatment of chronic 
migraine: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 
2017;16(6):425-434.


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12.
Appendices


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Appendix 1.
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 (study) drug, whether or not related 
to the medicinal (study) drug.
AI
autoinjector
AMY1
amylin 1
ANCOVA
analysis of covariance
blinding/masking
A single-blind study is one in which the investigator and/or staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/or staff and the patient are not.
BSFS
Bristol Stool Form Scale
CGRP
calcitonin gene-related peptide
CIOMS
Council for International Organizations of Medical Sciences
complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRP
clinical research physician: Individual responsible for the medical conduct of the 
study.  Responsibilities of the CRP may be performed by a physician, clinical research 
scientist, global safety physician, or other medical officer.
CRS
clinical research scientist
CSR
clinical study report
CTT
colonic transit time
eCOA
electronic clinical outcome assessment is a method of capturing data electronically in 
clinical trials.
eCRF
electronic case report form


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Term
Definition
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
Good Clinical Practice
GET
gastric emptying time
GI
gastrointestinal
GSRS
Gastrointestinal Symptom Rating Scale
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed, and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment 
groups, that is conducted before the final reporting database is created/locked.
ITT
intent to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (i.e., 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
mAb
monoclonal antibodies
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed effects model for repeated measures
MRI
magnetic resonance imaging
PT
Preferred Term
SAE
serious adverse event
SAP
statistical analysis plan


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Term
Definition
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.
SBTT
small bowel transit time
SBM
spontaneous bowel movement
SLBTT
combined small and large bowel transit time
SOC
System Organ Class
study treatment
Any treatment(s), in this case marketed product(s), intended to be administered to a 
study participant according to the study protocol
SUSAR
suspected unexpected serious adverse reaction
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens 
relative to the pretreatment state, and does not necessarily have to have a causal 
relationship with this treatment.
WGTT
whole gut transit time
WMC
wireless motility capsule or the SmartPillTM


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Appendix 2.
Study Governance Considerations


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Appendix 2.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 2.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential 
risks and benefits of participating in the study, and that their participation is 
voluntary.

ensuring that informed consent is given by each patient or legal 
representative.  This includes obtaining the appropriate signatures and dates 
on the informed consent form (ICF) prior to the performance of any protocol 
procedures and prior to the administration of study treatment.

answering any questions the patient may have throughout the study and 
sharing in a timely manner any new information that may be relevant to the 
patient’s willingness to continue his or her participation in the study.

ensuring that a copy of the ICF is provided to the participant or the 
participant’s legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the 
date the written consent was obtained. The authorized person obtaining the 
informed consent must also sign the ICF.
Appendix 2.1.2.
Recruitment
Lilly is responsible for the central recruitment strategy for patients.  Individual investigators may 
have additional local requirements or processes.
Appendix 2.1.3.
Ethical Review
The investigator must give assurance that the ethical review board (ERB) was properly 
constituted and convened as required by International Council for Harmonisation (ICH) 
guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with

the protocol and related amendments and addenda, current Investigator’s
Brochure for galcanezumab, US Product Information for erenumab, and 
updates during the course of the study

ICF, and


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
other relevant documents (e.g., curricula vitae, advertisements).
Appendix 2.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines, and

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 2.1.5.
Investigator Information
Investigators in this clinical trial should be neurologists, headache specialists, or other specialists 
with experience in headache clinical trials and treating patients with migraine.
Appendix 2.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 2.1.7.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
An investigator selected by the study team will serve as the CSR coordinating investigator.  If 
this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the CSR coordinating investigator.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 2.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will

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 case report 
forms (CRFs), and study procedures.


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
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 CRF data and use standard computer edits to detect errors in 
data collection, and

conduct a quality review of the database.
In addition, Lilly or its representatives will periodically check a sample of the patient data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 2.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Investigator sites will have continuous access to the electronic clinical outcome assessment
(eCOA) source documents during the study and will receive an archival copy at the end of the 
study for retention.
Any data for which the eCOA instruments 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 will be encoded and stored in a clinical trial database.  eCOA data read by 
a central reader, such as the WMC test, will be stored electronically. Subsequently, these data 
will be transferred from the central reader to the Lilly data warehouse.
Any data for which paper documentation provided by the patient will serve as the source 
document will be identified and documented by each site in that site’s study file.  Paper 
documentation provided by the patient may include, for example, a paper diary to collect 
patient-reported outcome measures (e.g., a rating scale).
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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Appendix 2.3.
Study and Site Closure
Appendix 2.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Appendix 2.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.
Appendix 2.4.
Publication Policy
The publication policy for Study I5Q-MC-CGBC is described in the Clinical Trial Agreement.


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Appendix 3.
Protocol Amendment
I5Q-MC-CGBC(a) Summary
A Phase 4 Single-Blind Study of Gastrointestinal Transit 
Time in Adult Patients with Migraine Before and After 
Initiation of a mAb CGRP Antagonist
Overview
Protocol I5Q-MC-CGBC(a) A Phase 4 Single-Blind Study of Gastrointestinal Transit Time in 
Adult Patients with Migraine Before and After Initiation of a mAb CGRP Antagonist has been 
amended.  The new protocol is indicated by amendment (a) and will be used to conduct the study 
in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:


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Amendment Summary for Protocol I5Q-MC-CGBC Amendment (a)
Section # and Name
Description of Change
Brief Rationale
Global
The study has been amended from an open-
label study to a single-blind study.
This change was made to reduce potential for patient bias, as the frequency and 
consequences of constipation for erenumab and galcanezumab are not the same 
based on a recent USPI update for erenumab regarding constipation.
Minor editorial changes
Minor editorial changes were made to improve clarity.
Title
CGRP Antagonist has been clarified to mAb 
CGRP Antagonist.
This clarification was made due to the recent approval of oral CGRP antagonists.
Section 2 Schedule of 
Activities
Vital sign assessments have been added to 
Visits 3, 4, and 5.
The additional vital sign assessments were added due to the April 2020 update to 
the erenumab USPI with Warning and Precautions language for new-onset or 
worsening of pre-existing hypertension based on postmarketing information.
Section 6.1 Inclusion 
Criteria
Chronic migraine has been removed from 
Inclusion Criterion [2].
The chronic migraine diagnosis was removed because this patient population has a 
higher frequency of headaches per month, which can be associated with more 
comorbidity.  Therefore, this change was made to reduce variation in the 
population due to the small sample size and the exploratory nature of the study.  
Chronic migraine was also removed from Inclusion Criterion [4] due to this 
change.
Inclusion Criterion [3] has been added.
The Inclusion Criterion [3] (that patients must have a frequency of less than 15 
monthly migraine headache days of which up to 14 can be migraine headache days) 
was added in response to the removal of chronic migraine from Inclusion Criterion
[2].
Section 6.2 Exclusion 
Criteria
Exclusion Criterion [21] has been changed 
from “Patients with a body mass index of 
≥50 kg/m2” to“Patients with a body mass 
index (BMI) of ≥40 kg/m2.”
The BMI criteria was amended to be consistent with the BMI thresholds in the 
previously conducted Phase 3 trials. This change will limit the potential for 
outliers.
Exclusion Criterion [28] has been added.
Having received oral CGRP antagonists has been added as an exclusion criterion
due to their recent approval for the acute treatment of migraine. The half-lives of 
oral CGRP antagonists are in the range of 5 to 12 hours, so a 14-day washout 
period was considered appropriate to ensure a complete washout before a patient 
enters the study.


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Section # and Name
Description of Change
Brief Rationale
Section 6.4 Screen 
Failures
Exclusion Criterion [27] and [28] has been 
added to the statement, “Patients using a 
concomitant medication that requires a stable 
dose for a specific duration prior to Visit 1 
may be rescreened if additional time is needed 
to meet the duration requirement.”
These Exclusion Criterion were added so that patients may be rescreened if 
additional time is needed to meet the specific medication duration requirement.
Section 7.1 
Treatments 
Administered
The 140 mg/mL dose of erenumab has been
updated to 2 consecutive doses of 70 mg/mL 
each.
This change was made to support the patient blinding so that each patient receives
2 injections.  This change also occurs in Section 7.1.1 (Packaging and Labeling).
Section 7.2 Method of 
Treatment Assignment
Stratification of randomization has been
amended from migraine classification of 
episodic or chronic and concurrent migraine 
preventive treatment to baseline migraine 
frequency and BMI category.
Baseline migraine frequency was added, as chronic migraine has been removed 
from the inclusion criteria.  Since chronic migraine is excluded, it is expected that 
fewer patients will be on a concurrent migraine preventive treatment.  Therefore, 
migraine preventive treatment has been removed as a stratification factor.  BMI 
category (<30 kg/m2, ≥30 kg/m2) was added to reduce any imbalance of outliers 
across the 2 treatment groups.  This change has also been made in Section 10.3.3.1 
(Primary Analyses).
The statement, “The study treatment will be 
administered only once at Visit 3 after 
expulsion of the WMC has been confirmed” 
has been amended to “The study treatment
will be administered only once at Visit 3.”
This statement was amended because administering the study treatment is not 
dependent on the expulsion of the WMC.
Section 7.3 Blinding
This section has been amended to clarify that 
Study CGBC is now single blind.
Additions were made to this section due to Study CGBC changing from an open-
label to a single-blind study so that the patient does not know treatment 
randomization.
Section 9.1.1 Primary 
Assessment of GI 
Transit Time
The statement, “Once enrolled into study, the 
patient will be asked to eat a SmartBar with 
120 mL water, followed by ingesting the 
WMC with 50 mL of water” has been
amended to “Once enrolled into study, the 
patient will be asked to eat a SmartBar, 
followed by ingesting the WMC with 120 mL 
of water.”
This statement was amended due to a discrepancy with the SmartPill Manual.  The 
correction was made to align with the manual (Medtronic 2017).


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Section # and Name
Description of Change
Brief Rationale
Section 9.2.1 Serious 
Adverse Events
The statement, “Patients with a serious hepatic 
AE should have additional data collected 
using the eCRF” has been removed.
This statement was removed because hepatic laboratory values are not being 
collected in this study.
Section 9.2.1.1 
Suspected Unexpected 
Serious Adverse 
Reactions
The statement, “Suspected unexpected serious 
adverse reactions (SUSARs) are serious 
events that are not listed in the IB and that the 
investigator identifies as related to study 
treatment or procedure” has been amended to 
“Suspected unexpected serious adverse 
reactions (SUSARs) are serious events that are 
not listed in the galcanezumab IB or the 
erenumab US package insert (USPI) and that 
the investigator identifies as related to study 
treatment or procedure.”
This statement was amended to clarify what will be considered a SUSAR for both 
galcanezumab and erenumab.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
“open-label” is replaced by “single-blind” throughout the document and each 
instance is not identified with strikethrough/underscore.
Minor formatting and editorial changes have been made throughout the document 
and each instance is not identified with strikethrough/underscore.
Protocol I5Q-MC-CGBC
A Phase 4 Open-LabelSingle-Blind Study of Gastrointestinal 
Transit Time in Adult Patients with Migraine Before and After 
Initiation of a mAb CGRP Antagonist
2.
Schedule of Activities
Table CGBC.2.1.
Schedule of Activities
Study Period
SP I
Screening 
and 
Baseline 
GI 
Transit 
Time
SP II
Single-BlindOpen-Label
Treatment and Post 
WMC Evaluation
Notes
Visit
V1
V2
V3
V4
V5
Vital signs
X
X
X
X
Includes body temperature, sitting blood 
pressure, and pulse.
3.3.
Benefit/Risk Assessment
Erenumab is a human monoclonal antibody that antagonizes the CGRP receptor.  The efficacy of 
erenumab for the prevention of migraine has been demonstrated in three Phase 3 randomized, 
double-blind trials (Goadsby et al. 2017; Tepper et al. 2017; Dodick et al. 2018).  Erenumab 70 
and 140 mg were both found to be effective in reducing the number of monthly migraine days in 
patients with episodic and chronic migraine.  No serious safety concerns were identified with a 
clear causal relationship to erenumab.  The incidences of SAEs and discontinuations due to AEs 
were low, and the most common adverse reactions (with an incidence of at least 2% for either 
dose of erenumab and at least 2% greater than placebo) were injection site reactions, 
constipation, and cramps/muscle spasms (Aimovig package insert, 2019; Ashina et al. 2019;
Aimovig package insert, 2020).  Hypersensitivity reactions, (including rash, angioedema, and 
anaphylaxis), as well as constipation with serious complications, and new-onset or worsening of 
pre-existing hypertension have been reported with erenumab in postmarketing experience.


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5.1.
Overall Design
Abbreviations:  GI = gastrointestinal; LD = loading dose; Single-Blind = only the 
investigator, site personnel, and sponsor will know the randomized treatment after 
randomization; SP = study period; TT WMC = wireless motility capsuletransit time.
Figure CGBC.5.1.
Illustration of study design for Clinical Protocol I5Q-MC-CGBC.
Study Period II:  At the start of the single-blindopen-label treatment period (Visit 3), patients 
will be randomized in a 1:1 ratio to receive galcanezumab 240 mg loading dose or erenumab 
140 mg.  Patients will be administered 2 galcanezumab injections of 120 mg each to achieve the 
240-mg loading dose or a single2 erenumab injections of 70 mg each to achieve the 140-mg 
dose.  At Visit 4, an additional WMC and recorder will be given to patients following
calibration.  Patients will exit the study at Visit 5.
5.5.
Justification for Dose
A galcanezumab 240-mg loading dose (2 consecutive injections of 120 mg each) or a dose of 
140 mg erenumab (2 consecutive injections of 70 mg each) will be administered by subcutaneous 
injection because both galcanezumab and erenumab have been approved in the US at these 
respective doses for migraine prevention.
6.1.
Inclusion Criteria
[2]
Have a diagnosis of migraine (1.1 and 1.2 ICHD), with or without aura, or 
chronic migraine, as determined by the study investigator and in consideration 
of International Headache Society International Classification of Headache 
Disorders – 3rd edition guidelines (ICHD-3 2018).
[3]
Have a frequency of less than 15 monthly headache days of which up to 14 
can be migraine headache days.


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[43] Patients can be on no more than 1 other migraine preventive treatment (except 
for tricyclic antidepressants and verapamil) as long as: 

that patient has had a stable dose of the oral migraine preventive treatment for a 
minimum of 2 months 
or

patients with chronic migraine that have recevied onabotulinumtoxinA for  a 
minimum of 2 cycles prior to Visit 1.
6.2.
Exclusion Criteria
[210]
Patients with a body mass index (BMI) of ≥50 40 kg/m2.
[276]
Patients currently receiving a mAb CGRP antagonist on CGRP 
antagonists or have takenreceived a mAb CGRP antagonist within the past 6 
months prior to Visit 1.
[28]
Have received an oral CGRP antagonist (gepant) 14 days prior to Visit 1.
6.4.
Screen Failures

Exclusion criterion 27, 28, and 31:  Patients using a concomitant medication that 
requires a stable dose for a specific duration prior to Visit 1 may be rescreened if 
additional time is needed to meet the duration requirement.
7.1.
Treatments Administered
Table CGBC.7.1.
Treatment Regimens
Regimen
Dose
Day 7 ± 2
Galcanezumab 240 mg
240 mg
(2 120-mg SC injection)
Erenumab 140 mg
140 mg
(21 70140-mg SC injection)
Abbreviation:  SC = subcutaneous.
7.2.
Packaging and Labeling
Galcanezumab and erenumab will be supplied as an injectable solution in 1-mL, single-dose, 
prefilled, disposable AI pen. Each AI pen of galcanezumab is designed to deliver 120 mg/mL, 
and each AI pen of erenumab is designed to deliver 140 70 mg/mL. All AI pens will be supplied 
in single pen cartons, with the site to select the appropriate quantity of AI pens, specific to the 
planned treatment schedule. Two galcanezumab AI pens are needed for the galcanezumab (240 
mg) treatment.  One Two erenumab AI pens areis needed for the erenumab (140 mg) treatment.


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7.2.
Method of Treatment Assignment
To achieve between-group comparability, the randomization will be stratified by site, concurrent 
migraine preventive treatmentBMI category (Yes/No<30 kg/m2, ≥30 kg/m2), and by baseline 
migraine frequency (<8 migraine headache days versus ≥8 migraine headache days)migraine 
classification of episodic or chronic.
7.2.1. Selection and Timing of Doses
The study treatment will be administered only once at Visit 3 after expulsion of the WMC has 
been confirmed.
7.3.
Blinding
This is an open-labelsingle-blind study.  Only the investigator, site personnel, and sponsor will 
know the randomized treatment after randomization.  Site Personnel are responsible to ensure 
patients remain blinded to treatment (i.e., patients must not see the AI pens before, during, or 
after the drug administration).  See the Manual of Operations for further details regarding 
blinding.
9.1.1. Primary Assessment of GI Transit Time
The WMC (Medtronic 2017) measures whole gut and regional gut (stomach, small bowel, and 
colon) transit times through measurement of pH, pressure, and temperature throughout the GI 
tract.  Once enrolled into study, the patient will be asked to eat a SmartBar with 120 mL water, 
followed by ingesting the WMC with 120 mL of water with 50 mL of water.  The patient will 
then be instructed to fast for an additional 6 hours after the WMC is administered and wear an 
external data recorder for up to 5 days. The WMC is a 4.5-g indigestible single-use, 27 12 mm 
cylindrical capsule.  Data are transferred to the accompanied wearable external data recorder and 
displayed and analyzed using MotiliGI™ version 3.1 software (Medtronic 2017).
9.2.1. Serious Adverse Events
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 by official notification on study-specific SAE forms.  This 24-
hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Patients with a serious hepatic AE should have additional data collected using the 
eCRF.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the galcanezumab IB or the erenumab US package insert (USPI) and that the investigator 
identifies as related to study treatment 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 


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procedures that will be followed for the identification, recording, and expedited reporting of 
SUSARs that are consistent with global regulations and the associated detailed guidances.
10.3.3.1.
Primary Analyses
The primary analysis will be performed using an analysis of covariance (ANCOVA) model.  The 
analysis will include the categorical effects of treatment and all randomization stratification 
factors (site, concurrent use of migraine preventive treatment Yes vs No, and migraine 
classification of episodic or chronicbaseline migraine frequency, and BMI category; see Section 
7.2), as well as the continuous baseline CTT.  Least squares mean change from baseline in each 
treatment group will be tested to detect any change in CTT between pre- and post-drug 
administration.
Appendix 1.
Abbreviations and Definitions
Term
Definition
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the treatment 
but the investigator and/his staff and the patient are not.
mAb
monoclonal antibodies


Leo Document ID = 98aeda5c-e244-43bf-a461-277a14f455da
Approver: 
Approval Date & Time: 19-May-2020 18:24:39 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 19-May-2020 19:42:40 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
 
 
 
Statistical Analysis Plan: I5Q-MC-CGBC (v2) 
 
 
A Phase 4 Single-Blind Study of Gastrointestinal Transit Time in 
Adult Patients with Migraine Before and After Initiation of a mAb 
CGRP Antagonist. 
 
 
NCT04294147 
 
 
Approval Date: 29-Sep-2020 


I5Q-MC-CGBC Statistical Analysis Plan Version 2
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LY2951742
1.
Statistical Analysis Plan
I5Q-MC-CGBC:  A Phase 4 Single-Blind Study of 
Gastrointestinal Transit Time in Adult Patients with 
Migraine Before and After Initiation of a mAb CGRP 
Antagonist 
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-gnlm (LY2951742) Migraine
A multicenter, randomized, single-blind, Phase 4 study with 2 study periods in patients with 
migraine who are deemed eligible for preventive treatment by the study investigator.  The 
study has 2 periods: a screening period to determine patient eligibility and lead-in with a 
baseline WMC test; and a single-blind treatment period with post–study treatment 
WMC test.  
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I5Q-MC-CGBC
Statistical Analysis Plan Version 1 electronically signed and approved by Lilly:  
12 March 2020
Statistical Analysis Plan Version 2 electronically signed and approved by Lilly on date 
provided below.
Approval Date: 29-Sep-2020 GMT


I5Q-MC-CGBC Statistical Analysis Plan Version 2
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan I5Q-MC-CGBC:  A Phase 4 Single-Blind 
Study of Gastrointestinal Transit Time in Adult Patients with 
Migraine Before and After Initiation of a mAb CGRP Antagonist.......................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
4.1.
Primary Objective ..........................................................................................................8
4.2.
Secondary and Tertiary Objectives .................................................................................8
5.
Study Design.....................................................................................................................10
5.1.
Summary of Study Design............................................................................................10
5.2.
Determination of Sample Size ......................................................................................10
5.3.
Method of Assignment to Treatment ............................................................................11
5.4.
Measures......................................................................................................................11
5.4.1.
Primary Measures ................................................................................................11
5.4.2.
Other Secondary Measures...................................................................................11
6.
A Priori Statistical Methods ..............................................................................................13
6.1.
General Considerations ................................................................................................13
6.2.
Adjustments for Covariates ..........................................................................................13
6.3.
Handling of Dropouts or Missing Data.........................................................................13
6.4.
Multicenter Studies ......................................................................................................13
6.5.
Multiple Comparisons/Multiplicity...............................................................................14
6.6.
Analysis Populations....................................................................................................14
6.7.
Patient Disposition .......................................................................................................14
6.8.
Patient Characteristics ..................................................................................................14
6.9.
Concomitant Therapy...................................................................................................15
6.10. Efficacy Analyses ........................................................................................................15
6.10.1.
Primary Outcome and Methodology.....................................................................15
6.10.2.
Secondary and Tertiary Efficacy Analyses ...........................................................15
6.10.3.
Sensitivity Analyses.............................................................................................16
6.10.4.
Exploratory Analyses...........................................................................................16
6.11. Safety Analyses............................................................................................................17
6.11.1.
Extent of Exposure...............................................................................................17
6.11.2.
Treatment Compliance .........................................................................................17
6.11.3.
Adverse Events ....................................................................................................18
6.11.4.
Serious Adverse Events and Other Notable Adverse Events .................................18


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6.11.5.
Clinical Laboratory Evaluation.............................................................................18
6.11.6.
Vital Signs and Other Physical Findings...............................................................19
6.11.7.
Electrocardiograms ..............................................................................................20
6.12. Blinding .......................................................................................................................20
6.13. Subgroup Analyses.......................................................................................................20
6.14. Important Protocol Deviations......................................................................................20
6.15. Annual Report Analyses...............................................................................................21
6.16. Clinical Trial Registry Analyses...................................................................................21
7.
References ........................................................................................................................22
8.
Appendices .......................................................................................................................23


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Table of Contents
Table
Page
Table CGBC.4.1.Secondary and Tertiary Objectives and Endpoints ...........................................8
Table CGBC.6.1.Criteria for Categorical Changes of Interest in Vital Signs .............................20


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Table of Contents
Figure
Page
Figure CGBC.5.1.
Illustration of study design for Clinical Protocol I5Q-MC-CGBC. ............10


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Table of Contents
Appendix
Page
Appendix 1.
Description of Important Protocol Deviations ................................................24


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3.
Revision History
Statistical Analysis Plan Version 1 was approved prior to the first patient visit.  
Statistical Analysis Plan Version 2 was approved prior to the first patient visit.  The following 
updates were made to coincide with a protocol amendment:

Section 5.1 and throughout, updated to single-blind study as the protocol was updated to 
a single-blind study design.

Section 5.3 and throughout, updated stratification factors.  Removed concurrent migraine 
preventive treatment (Yes/No) and migraine classification of episodic or chronic; and 
replaced with body mass index category (<30kg/m2, ≥30 kg/m2), and by baseline 
migraine frequency (<8 migraine headache days, ≥8 migraine headache days).

Section 6.2, with the removal of chronic migraine patients, the derivation of chronic 
versus episodic has been removed.

Section 6.3 was updated to include language about adjustments due to COVID-19.  

Section 6.8, substance use, medical history, and preexisting conditions were added to
patient characteristics.  

Section 6.11, vital signs bullet was added, and a description of models used for safety 
analyses was provided.

Section 6.11.2, treatment compliance was moved to this section.

Section 6.11.6, analyses for vital sign data were added; previously no analyses were 
planned.

Section 6.12, section on blinding was added since study design switched from open-label
to single-blind.

General formatting and grammatical edits were made throughout the document that did 
not change the meaning.


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4.
Study Objectives
4.1.
Primary Objective
The primary objective is to evaluate colonic transit time (CTT) in patients with migraine 1 week 
prior to and 2 weeks after administration of an initial loading dose of galcanezumab 240 mg or 
erenumab 140 mg.  The primary outcome measure is CTT in hours.  The primary endpoint is the 
change from baseline in CTT after administration of galcanezumab or erenumab within each 
treatment group in hours at the end of Week 2.  
4.2.
Secondary and Tertiary Objectives
Table CGBC.4.1 shows the secondary and tertiary objectives and endpoints.
Table CGBC.4.1.
Secondary and Tertiary Objectives and Endpoints
Objectives
Endpoints
Secondary Objectives
To evaluate transit time of the following segments of the 
gastrointestinal (GI) tract 1 week prior to and 2 weeks after 
administration of galcanezumab or erenumab:

whole gut

gastric emptying

small intestine, and 

combined small and large bowel.
Change from baseline in GI transit time in each of the following 
segments after administration of galcanezumab or erenumab within 
each treatment group at the end of Week 2:

whole gut transit time (WGTT), in hours

gastric emptying time (GET), in hours

small intestine bowel transit time (SBTT), in 
hours, and 

combined small and large bowel transit time 
(SLBTT), in hours.
To evaluate the frequency of contractions, motility index,
and area under the pressure curve (AUC) by quartile in the 
colon to assess for correlation with colonic transit time
(CTT) results.
Changes in pressure parameters from baseline:

contraction freq/min

motility index = ln (# of contractions × ∑pressure 
amplitudes +1), and   

Area under the pressure curve (AUC).
To evaluate number of weekly spontaneous bowel 
movements (un-aided by laxatives, enemas, or 
suppositories) prior to and after administration of 
galcanezumab or erenumab.
Change from baseline in number of weekly spontaneous bowel 
movements after administration of galcanezumab or erenumab 
within each treatment group at Weeks 2 and 4 post-treatment.
To evaluate GI symptom rating scale (GSRS) prior to and 
after administration of galcanezumab or erenumab.
Change from baseline in GSRS after administration of galcanezumab 
or erenumab within each treatment group at Weeks 2 and 4 
post-treatment.
To evaluate the Bristol Stool Form Scale (BSFS) prior to 
and after administration of galcanezumab or erenumab.
Change from baseline in BSFS after administration of galcanezumab 
or erenumab within each treatment group at Weeks 2 and 4 
post-treatment.


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Secondary and Tertiary Objectives and Endpoints
Objectives
Endpoints
Tertiary/Exploratory Objectives
To evaluate the transit time between galcanezumab and 
erenumab for

whole gut 

gastric emptying

small bowel

colon, and 

combined small and large bowel.
Change from baseline in transit time after administration of 
galcanezumab or erenumab between treatment groups at the end of 
Week 2 for

WGTT, in hours

GET, in hours

SBTT, in hours 

CTT, in hours, and

combined SLBTT, in hours.
To evaluate number of weekly spontaneous bowel 
movements (un-aided by laxatives, enemas, or 
suppositories) prior to and after administration of 
galcanezumab or erenumab. 
Change from baseline in number of weekly spontaneous bowel 
movements after administration of galcanezumab or erenumab 
between each treatment group at Weeks 2 and 4 post-treatment.
To evaluate GSRS prior to and after administration of 
galcanezumab or erenumab.
Mean change difference from baseline in GSRS scores after 
administration of galcanezumab or erenumab between treatment 
groups at Weeks 2 and 4 post-treatment.
To evaluate the BSFS prior to and after administration of 
galcanezumab or erenumab.
Mean change difference from baseline in BSFS scores after 
administration of galcanezumab or erenumab between treatment 
groups at Weeks 2 and 4 post-treatment.


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5.
Study Design
5.1.
Summary of Study Design
Study I5Q-MC-CGBC is a multicenter, randomized, single-blind, Phase 4 study with 2 study 
periods in patients with migraine who are deemed eligible for preventive treatment by the study 
investigator.  The study has 2 periods:  a screening period to determine patient eligibility and 
lead-in with a baseline wireless motility capsule (WMC) test and a single-blind treatment period 
with a post-study treatment WMC test.
Figure CGBC.5.1 illustrates the study design.
Abbreviations:  LD = loading dose; SP = study period; WMC = wireless 
motility capsule.
Note:  Single-Blind - only the investigator, site personnel, and sponsor will know the 
randomized treatment after randomization.
Figure CGBC.5.1.
Illustration of study design for Clinical Protocol I5Q-MC-CGBC.
5.2.
Determination of Sample Size
Assuming that the within-group mean difference in CTT is approximately 4.2 hours with a 
standard deviation of approximately 8, a sample of 30 patients in each treatment group will 


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provide 80% power to detect the difference within the treatment group.  The total sample size for 
the study is 60 patients.
Assuming a 20% screen failure rate, approximately 75 patients may be screened to enroll
60 patients in the study. Eligible patients will be randomized in a 1:1 ratio to galcanezumab or 
erenumab to enroll approximately 30 patients in each treatment group.
5.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomized to single-blind treatment at 
Visit 3 in a 1:1 ratio to galcanezumab or erenumab.  To achieve between-group comparability, 
the randomization will be stratified by site, body mass index (BMI) category (<30kg/m2, ≥30 
kg/m2), and by baseline migraine frequency (<8 migraine headache days, ≥8 migraine headache 
days).  Assignment to treatment groups will be determined by a computer-generated random 
sequence using an interactive web-response system.
5.4.
Measures
5.4.1. Primary Measures
The SmartPill™WMC technology (Medtronic, Minneapolis, MN, USA) will be used to evaluate 
total gastrointestinal (GI) transit time and segmental transit time.  The WMC measures whole gut 
and regional gut (stomach, small bowel, and colon) transit times through measurement of pH, 
pressure, and temperature throughout the GI tract.  Once enrolled in the study, patients will be 
asked to eat a SmartBar, followed by ingesting the WMC with 120 mL of water.  Patients will be 
instructed to fast for an additional 6 hours after ingesting the WMC and to wear an external data 
recorder for up to 5 days.  The WMC is a 4.5-g indigestible, single-use, 27 12 mm cylindrical 
capsule.  Data will be transferred to the wearable external data recorder and displayed and 
analyzed using Medtronic MotiliGI™ version 3.1 software (Medtronic, Minneapolis, MN, 
USA).  
The baseline and postbaseline WMC tests will be assessed by expert readers who are blind to 
treatment assignment.
The primary outcome measure is CTT in hours.  Secondary transit time outcome measures 
include the whole gut transit time in hours, gastric emptying time (GET) in hours, small intestine 
bowel transit time (SBTT) in hours, and small and large bowel transit time (SLBTT) in hours.  
All transit time outcome measures will be collected at baseline and 2 weeks after study drug 
administration.
Further secondary outcome measures include contraction, measured as frequency per minute, 
motility index, and AUC.  
5.4.2. Other Secondary Measures
Gastrointestinal Symptom Rating Scale:  The Gastrointestinal Symptom Rating Scale (GSRS) 
is a validated 15-item questionnaire that evaluates the 5 common symptoms of GI disorders:  
abdominal pain, reflux, indigestion, constipation, and diarrhea.  Items contain questions about 


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the past week using a 7-point categorical response scale ranging from no discomfort to very 
severe discomfort (Revicki et. al 1998; Khanna et al. 2017).  Based on a factor analysis, the 
15 GSRS items are summarized by the 5 scales, which are calculated by taking the mean of the 
items completed within an individual scale.  The GSRS is grouped accordingly by

abdominal pain – abdominal pain, hunger pains, and nausea

reflux syndrome – heartburn and acid reflux

diarrhea syndrome – diarrhea, loose stools, and urgent need to have a bowel movement

indigestion syndrome – rumbling, bloating, belching, and increased flatus
(breaking wind); and

constipation syndrome – constipation, hard stools, and sensation of not completely 
emptying the bowels.
Bristol Stool Form Scale:  The Bristol Stool Form Scale (BSFS) is 7-point ordinal scale of stool 
types ranging from the hardest (type 1) to the softest (type 7).  Symptoms of constipation are 
related to harder stools (types 1 and 2), and symptoms of diarrhea are related to loose/liquid 
stools (types 6 and 7).  Overall, stool types 3 to 5 are considered normal.  The BSFS provides the 
patient with a pictorial representation of each type of stool (Blake et al. 2016).
Spontaneous Bowel Movement Frequency Evaluation:  The spontaneous bowel movement 
(SBM) frequency evaluation is the number of spontaneous (nonintervention induced) bowel 
movements that a patient has had in the past 7 days.  Patients are asked how many SBMs they 
have had in the past 7 days, and the information is collected on the case report form (CRF) for
Visits 1, 3, 4, and 5.


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6.
A Priori Statistical Methods
6.1.
General Considerations
General aspects of statistical analyses are described below.
Unless otherwise specified, analyses will be conducted for the intent-to-treat (ITT) population,
which includes all patients who are randomized and receive at least 1 dose of study treatment. 
Patients in the ITT population will be analyzed according to the treatment group to which they 
are randomized. The ITT population will be the primary population for which statistical analysis 
are performed. When mean change from baseline is assessed, only patients with baseline and 
postbaseline measurements will be included in the analysis.
Investigative sites with fewer than 4 randomized patients per treatment group will be pooled for 
statistical analysis purposes.
All tests of within-group and between-group comparisons will be conducted at a 2-sided alpha 
level of 0.05, unless otherwise stated.
6.2.
Adjustments for Covariates
The analysis of covariance (ANCOVA) model will include the categorical effects of treatment, 
pooled investigative site, BMI category (<30kg/m2, ≥30 kg/m2), and baseline migraine 
frequency (<8 migraine headache days, ≥8 migraine headache days), as well as the continuous 
baseline value.  Rules for pooling of investigative sites are described in Section 6.4.
For continuous measures with repeated postbaseline measurements, change from baseline will be 
analyzed using a restricted maximum likelihood (REML)–based mixed effects model for 
repeated measures (MMRM) technique.  The analysis will include the fixed categorical effects of 
treatment, pooled investigative site, BMI category (<30kg/m2, ≥30 kg/m2), baseline migraine 
frequency (<8 migraine headache days, ≥8 migraine headache days), week, and 
treatment-by-week interaction, as well as the continuous fixed covariates of baseline value and 
baseline-by-week interaction.  
6.3.
Handling of Dropouts or Missing Data
For the repeated measures analyses, the model parameters are simultaneously estimated using
restricted likelihood estimation incorporating all of the observed data.  Estimates have been
shown to be unbiased when data are missing at random (MAR).  Missingness due to COVID-19 
does not depend on the outcome measurements and therefore will be considered MAR. 
6.4.
Multicenter Studies
Investigative sites with fewer than 4 randomized patients per treatment group will be pooled for 
analyses.  If a pooled site has fewer than 4 randomized patients per treatment group, the site will 
be pooled with the next smallest site, determined to be the site with the smallest number of 
randomized patients, or if more than one site meets that criterion, the smallest site with the 
lowest investigator number.  This process will continue until all pooled sites have 4 or more 
randomized patients per treatment group.


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All analyses that are prespecified to include investigative site will use this pooled investigative 
site.  The investigative site numbers will be included in the listings.
6.5.
Multiple Comparisons/Multiplicity
All tests of within-group and between-group comparisons will be conducted at a 2-sided alpha 
level of 0.05, unless otherwise stated.
6.6.
Analysis Populations
Intent-to-treat (ITT) population:  All patients who are randomized and receive at least 1 dose 
of study treatment.  Patients in the ITT population will be analyzed according to the treatment 
group to which they are randomized.
Safety population:  All patients who are randomized and receive at least 1 dose of study 
treatment.  Patients in the safety population will be analyzed according to the treatment they 
receive.
Other populations may be explored if appropriate, such as the ITT population excluding patients 
taking prohibited medications that are known to have an effect on GI motility or the WMC test.
6.7.
Patient Disposition
The number and percentage of patients in the ITT population who complete the study or 
discontinue early will be summarized for both treatment groups.  A detailed description of 
patient disposition will be provided at the end of the study.
Patient allocation by investigative site will be summarized for the ITT population.  Patient 
allocation by investigative site will also be listed.
6.8.
Patient Characteristics
The following patient characteristics at baseline will be summarized by treatment group for the
ITT population:

demographics (age, gender, ethnic origin, height, weight, and BMI)

medical history and preexisting conditions

total gut and segmental transit times

GI symptom rating scale, SBM frequency, and BSFS, and

alcohol, tobacco, caffeine, and nicotine consumption.
Medical history and preexisting conditions will be summarized by descending frequency 
of Preferred Term (PT) nested within System Organ Class (SOC). Medical history is 
defined as illness(es) that ended prior to the signing of informed consent.  Preexisting 
conditions and adverse events (AEs) at baseline are those AEs occurring during the 
baseline/screening visits for the study period.
The percentage of patients who report a change in alcohol, tobacco, caffeine, or nicotine 
consumption during the study will be summarized.


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6.9.
Concomitant Therapy
The proportion of patients who received concomitant medication recorded on the general
concomitant medication electronic case report form (eCRF) will be summarized for the ITT 
population.  Treatment group comparisons, if needed, will be done using Fisher’s exact test.
Concomitant therapies are defined those that were stopped during Study Period II or continued in 
Study Period II.  If a medication was started and stopped on the same day as the first injection, 
it will be counted as a concomitant medication. If a medication was started before the first 
day of injection but was stopped on the same day of injection, it will not be counted as a 
concomitant medication.
6.10. Efficacy Analyses
6.10.1. Primary Outcome and Methodology
The primary analysis will evaluate the change from baseline in CTT (hours) after administration 
of an initial loading dose of galcanezumab 240 mg or erenumab 140 mg at the end of Week 2.
The primary analysis will be performed using an ANCOVA model including the categorical 
effects of treatment, pooled investigative site, BMI category (<30kg/m2, ≥30 kg/m2), and 
baseline migraine frequency (<8 migraine headache days, ≥8 migraine headache days), as well as 
the continuous baseline CTT (hours).
The primary endpoint of this study for galcanezumab 240 mg and erenumab 140 mg will be 
estimated as the least squares (LS) mean change from baseline to Week 2 from the ANCOVA
model.  The type I error rate for the study will be controlled at a 2-sided 0.05 level.
6.10.2. Secondary and Tertiary Efficacy Analyses 
The LS mean change from baseline to Week 2 in CTT (hours) between galcanezumab 240 mg 
and erenumab 140 mg will be compared to detect any between-group differences in the primary 
model described above.
For continuous secondary/tertiary measures with a single postbaseline measurement, analysis 
will be performed using an ANCOVA model.  The analysis will include the categorical effects of 
treatment and all randomization stratification factors, as well as the continuous baseline value.  
The LS mean change from baseline in each treatment group will be tested to detect any changes 
between pre- and post-treatment administration.  The LS mean change from baseline in the 
2 treatment groups will also be compared to detect any between-group differences.
For continuous efficacy measures with repeated postbaseline measurements, change from 
baseline will be analyzed using a REML-based MMRM technique.  The analysis will include the 
fixed categorical effects of treatment, pooled investigative site, BMI category (<30kg/m2, 
≥30 kg/m2), baseline migraine frequency (<8 migraine headache days, ≥8 migraine headache 
days), week, and treatment-by-week interaction, as well as the continuous fixed covariates of 
baseline value and baseline-by-week interaction.


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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 the
denominator degrees of freedom.  If the model does not converge, with both the Hessian and the 
G matrix being positive definite under the default fitting algorithm used by PROC MIXED, the 
Fisher scoring algorithm will be implemented by specifying the SCORING option in SAS®.  If 
the model still fails to converge, the model will be fit using covariance matrices of the following 
order specified by a decreasing number of covariance parameters until convergence is met:

heterogeneous Toeplitz

heterogeneous first-order autoregressive

Toeplitz, and

first-order autoregressive.
When the unstructured covariance matrix is not utilized, the sandwich estimator (Diggle and 
Kenward 1994) will be used to estimate the standard errors of the fixed-effects parameters.  The 
sandwich estimator is implemented by specifying the EMPIRICAL option in SAS.  When the 
sandwich estimator is utilized, the Kenward-Roger approximation for denominator degrees of 
freedom (Kenward and Roger 1997) 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.
6.10.3. Sensitivity Analyses 
The primary analysis assumes that data are normally distributed.  To assess the impact of the 
normality assumption, a nonparametric sensitivity analysis of the primary endpoint will be 
produced using the Wilcoxon signed rank test (Wilcoxon 1945) to compare the change from 
baseline within each treatment group.
6.10.4. Exploratory Analyses
If the within-treatment analyses of change from baseline in GET and SBTT are statistically 
significant for either treatment, the changes in pressure parameters (frequency of contractions, 
motility index, and AUC) will be assessed for both treatments for the stomach, antrum, 
duodenum, ileum, caecum, sigmoid, and small bowel (by quartile) using the ANCOVA model 
described in Section 6.10.2.
Colonic transit time (hours) for patients with treatment-emergent (TE) constipation versus those 
without TE constipation will be explored.  Treatment-emergent constipation is defined as 
reporting a treatment-emergent adverse event (TEAE) of constipation and/or score of ≥4 for 
constipation syndrome from the GSRS assessment.  Descriptive statistics and boxplots will be 
provided by TE constipation category (Yes vs No) for change from baseline in CTT (hours) by
treatment separately.  Furthermore, if 10 or more patients have TE constipation for each 
treatment, then ANCOVA analyses will be performed to evaluate the change from baseline in 
CTT (hours) between TE constipation categories at the end of Week 2 for each treatment.  The 
ANCOVA analyses will include the categorical effects of TE constipation, pooled investigative 


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site, BMI category (<30kg/m2, ≥30 kg/m2), and baseline migraine frequency (<8 migraine 
headache days, ≥8 migraine headache days), as well as the continuous baseline CTT (hours).
6.11. Safety Analyses
Unless specified otherwise, safety analyses outlined in the following subsections will be 
conducted for the safety population.  
The safety and tolerability of treatment will be assessed by summarizing

TEAEs
o
by PT
o
by PT nested within SOC
o
by maximum severity
o
by investigator classification of related to study treatment

serious adverse events (SAEs) by PT

AEs leading to discontinuation by PT, and

vital signs.
Baseline for all safety measures includes all data prior to injection of study treatment.  
Postbaseline includes all data in Study Period II from injection of study treatment to completion 
of Study Period II.
For safety categorical variables and categorical variables of demographics and baseline 
characteristics, comparisons between treatment groups will be performed using Fisher’s exact 
test. For continuous variables of demographics and baseline characteristics, an analysis of 
variance (ANOVA) with treatment as an independent variable in the model will be performed.  
6.11.1. Extent of Exposure
Patients will receive study treatment at the beginning of Visit 3.
The following information will be recorded on the eCRF for each dose:

confirmation that the patient received study treatment (including reason if 
study treatment was not administered), and 

date and time of administration.
A listing of patient exposure will be produced.  
6.11.2. Treatment Compliance
A by-patient listing of doses received will be generated, including dose date, number of 
injections, and location of injection.


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6.11.3. Adverse Events
Treatment-emergent AEs are defined as reported AEs that first occurred or worsened during the 
postbaseline phase compared with the baseline phase. For each TEAE, severity (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 TE computation. 
For each LLT, the maximum severity at baseline will be used as the baseline severity.  If the 
maximum postbaseline severity is greater than the maximum baseline severity, the event will be 
considered TE for the specific postbaseline period.
For each patient and TEAE, the maximum severity for the specified MedDRA level (PT, high 
level term, or SOC) will be 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 
include only patients from the specified gender.
6.11.4. Serious Adverse Events and Other Notable Adverse Events
An SAE is any AE that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of death)

persistent or significant disability/incapacity

congenital anomaly/birth defect, or

important medical events that may not be immediately life threatening or result in death 
or hospitalization but may jeopardize the patient or may require intervention to prevent 
one of the other outcomes listed in the definition.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.

When a condition related to the autoinjector (AI) pen necessitates medical or surgical 
intervention to preclude either permanent impairment of a body function or permanent 
damage to a body structure, the serious outcome of ‘required intervention’ will be 
assigned.
All SAEs will be summarized by PT.
6.11.5. Clinical Laboratory Evaluation
Investigators are responsible for the appropriate medical care of patients during the study and 
must document their review of each laboratory safety report.  Local urine pregnancy tests should 
be conducted according to the Schedule of Activities (see Section 2 of Protocol CGBC).


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Pregnancy (during maternal or paternal exposure to study treatment) does not meet the definition 
of an AE.
No analyses of clinical laboratory evaluations will be produced.
6.11.6. Vital Signs and Other Physical Findings
Vital signs collected during the study include systolic (SBP) and diastolic blood pressure (DBP), 
pulse, and temperature. Blood pressure and pulse measurements will be taken when the patient 
is in a sitting position. 
The number and percent of patients meeting criteria for categorical changes of interest in vital 
signs at any time during study will be summarized.  Treatment group comparisons will be 
performed using Fisher’s exact test.  
Table CGBC.6.1 displays the criteria for categorical changes of interest in vital signs.  The last 
column of the table displays the patient populations defined by baseline categories. 
The criteria to identify patients with TE abnormal changes generally consist of 2 parts:  an 
absolute threshold and a change from baseline amount.  

The absolute threshold in the criteria is based on 1) minimum postbaseline when the 
direction is low; 2) maximum postbaseline when the direction is high.  

The change from baseline amount in the criteria is 1) decrease from baseline to minimum 
postbaseline when the direction is low, and 2) increase from baseline to maximum 
postbaseline when the direction is high.
The baseline for SBP, DBP, pulse, and temperature is defined as the last non-missing baseline 
value during the baseline period.  This baseline definition for SBP, DBP, pulse, and temperature 
applies to all analyses (both continuous and categorical) for SBP, DBP, pulse, and temperature.  
Any clinically significant finding from vital sign measurements that results in a diagnosis and 
that occurs after the patient receives the first dose of study treatment should be reported as an AE 
via eCRF to Eli Lilly and Company or its designee.
Other physical findings will be collected at Visit 1. No analyses of other physical findings will 
be produced.


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Table CGBC.6.1.
Criteria for Categorical Changes of Interest in Vital Signs
Parameter
Direction
Criteria
Patient Population defined by 
Baseline Categories
Systolic BP (mm Hg) 
(sitting)
Low
≤90 and decrease ≥20
All patients; >90; 90
High
≥140 and increase ≥20
All patients; <140, 140
PCS High
≥180 and increase ≥20
All patients; <180; 180
Sustained 
Elevation
≥140 and increase ≥20 at 
2 consecutive visits
All patients; < 140; ≥140
Diastolic BP (mm Hg)
(sitting)
Low
≤50 and decrease ≥10
All patients; >50; 50
High
≥90 and increase ≥10
All patients; <90; 90
PCS High
≥105 and increase ≥15
All patients; <105; 105
Sustained 
Elevation
≥90 and increase ≥10 at 
2 consecutive visits
All patients; < 90; ≥90
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
All patients; 50; <50
High
>100 and increase ≥15
All patients; 100; >100
Sustained 
Elevation
>100 and increase ≥15 at 2 
consecutive visits
All patients; ≤100; >100
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. 
6.11.7. Electrocardiograms
Not applicable.
6.12. Blinding
This is a single-blind study.  Only the investigator, site personnel, and sponsor will know the 
randomized treatment after randomization.  Site personnel are responsible for ensuring that 
patients remain blinded to treatment (that is, patients must not see the AI pens before, during, or 
after the drug administration).  See the Manual of Operations for further details regarding 
blinding.
6.13. Subgroup Analyses
Not applicable.
6.14. Important Protocol Deviations
Important protocol deviations that potentially compromise data integrity or patients’ rights or 
safety will be summarized by treatment group for the ITT population.  Tables and listings of 


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important protocol deviations for the ITT population during all study phases will be provided by 
randomized treatment group.
Appendix 1 lists the categories, subcategories, and study-specific terms of important protocol 
deviations, as well as the source and method used to identify each deviation.  Per the study 
team’s discretion, for non-programmable protocol deviations, additional categories can be added 
to the final non-programmable protocol deviations list as deemed necessary.
6.15. Annual Report Analyses
Not applicable.  
6.16. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:

A summary of AEs will be provided as a dataset, which will be converted to an XML 
file.  Both SAEs and ‘Other’ AEs are summarized:  by treatment group, 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 SAE and ‘Other’ AE, for each term and treatment group, the following are provided:
o
number of participants at risk of an event
o
number of participants who experienced each event, and
o
number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in less
than 5% of patients in every treatment group may not be included if a 5% threshold is 
chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures (for example, the CSR 
and manuscripts).  


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7.
References
Blake MR, Raker JM, Whelan K. Validity and reliability of the Bristol Stool Form Scale in 
healthy adults and patients with diarrhoea-predominant irritable bowel syndrome. Aliment 
Pharmacol Ther. 2016;44(7):693-703.
Diggle P, Kenward MG. Informative drop-out in longitudinal data analysis (with discussion). 
Appl Stat. 1994;43(1):49-93.
Kenward MG, Roger JH. Small sample inference for fixed effects from restricted maximum 
likelihood. Biometrics. 1997;53(3):983-997.
Khanna D, Hays RD, Shreiner AB, Melmed GY, Chang L, Khanna PP, Bolus R, Whitman C, 
Paz SH, Hays T, Reise SP, Spiegel B. Responsiveness to change and minimally important 
differences of the patient-reported outcomes measurement information system gastrointestinal 
symptoms scales. Dig Dis Sci. 2017;62(5):1186-1192.
Medtronic. SmartPill™ GI Monitoring System: User Manual SmartPill™ Software v3.1. 
Minneapolis, MN; 2017.
Revicki DA, Wood M, Wiklund I, Crawley J. Reliability and validity of the Gastrointestinal 
Symptom Rating Scale in patients with gastroesophageal reflux disease. Qual Life Res. 
1998;7(1):75-83.
Wilcoxon F. Individual comparisons by ranking methods. Biometrics Bull. 1945:1(6):80-83.


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8.
Appendices


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Appendix 1.
Description of Important Protocol Deviations
Table CGBC.APP.1.1.
Description of Important Protocol Deviations
Category
Subcategory
Study-Specific 
Source 
Comments
Informed consent
Informed Consent Not 
Obtained
No reconsent for safety update
Non-programmable – Monitor identified
Procedure done prior to or without consent
Programmable – Statistics
Check that Visit 1 date is not 
before informed consent date
Eligibility
Inclusion/Exclusion
Age <18 or >55 years old at study entry
Programmable – Statistics
No diagnosis of migraine
Non-programmable – Monitor identified
On >1 other migraine preventive medication
Non-programmable – Study team 
identified
1) Stats will create the list of 
patients who meet this IPD 
criteria based on a list of 
medications from Medical.
2) Among those, the true IPDs 
will be manually added into a 
non-programmable excel sheet. 
Number of headache days ≥15 per 30 day period 
at baseline
Non-programmable – Monitor identified
Female patients with positive urine pregnancy test Non-programmable – Monitor identified
<3 bowel movements in the 7 days prior to Visit 1 Programmable – Statistics
History of IBS or chronic constipation
Programmable – Statistics
Hx bezoar, dysphagia, stricture, fistula, GI obst
Programmable – Statistics
History of GI surgery
Non-programmable – Monitor identified
History of abdominal surgery in past 3 months
Non-programmable – Monitor identified
History of bariatric surgery
Non-programmable – Monitor identified
History of Crohn’s, celiac, UC, or diverticulitis
Programmable – Statistics


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Description of Important Protocol Deviations
Category
Subcategory
Study-Specific 
Source 
Comments
Eligibility
Inclusion/Exclusion
Diagnosed with type 1 or type 2 diabetes
Programmable – Statistics
Have pacemakers or other electromechanical 
devices
Programmable – Statistics
BMI ≥40 kg/m2
Programmable – Statistics
Women who are pregnant or nursing
Non-programmable – Monitor identified
Drug/alcohol abuse within 1 year prior to Visit 1
Non-programmable – Monitor identified
Acute, serious, or unstable medical condition
Non-programmable – Monitor identified
History of cardiovascular events in past 6 months Non-programmable – Monitor identified
Suicidal or at significant risk for suicide
Non-programmable – Monitor identified
Taken mAb CGRP antagonist within past 6 
months
Non-programmable – Study team 
identified
1) Stats will create the list of 
patients who meet this IPD 
criteria based on a list of 
medications from Medical.
2) Among those, the true IPDs 
will be manually added into a 
non-programmable excel sheet.
Taken oral CGRP antagonist within 14 days
Non-programmable – Study team 
identified
1) Stats will create the list of 
patients who meet this IPD 
criteria based on a list of 
medications from Medical.
2) Among those, the true IPDs 
will be manually added into a 
non-programmable excel sheet.
Allergy to therapeutic proteins or CGRP 
antagonist
Non-programmable – Monitor identified
Allergic to SmartBar ingredients
Non-programmable – Monitor identified
Other inadvertent enrollment
Non-programmable – Monitor identified
Safety
SAEs
SAEs not reported in 24 hours
Non-programmable – Monitor identified
Administrative/ 
Oversight
Suspected Misconduct
Suspected fraud
Non-programmable – Monitor identified
Privacy breach
Non-programmable – Monitor identified


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Description of Important Protocol Deviations
Category
Subcategory
Study-Specific 
Source 
Comments
Administrative/ 
Oversight
Other
Quality issue at site or vendor
Non-programmable – Monitor identified
Study Procedures
Excluded Conmeds
Taking agents that affect GI motility
Non-programmable – Study team 
identified
1) Stats will create the list of 
patients who meet this IPD 
criteria based on a list of 
medications from Medical.
2) Among those, the true IPDs 
will be manually added into a
non-programmable excel sheet.
Taking CGRP antagonists
Non-programmable – Study team 
identified
1) Stats will create the list of 
patients who meet this IPD 
criteria based on a list of 
medications from Medical.
2) Among those, the true IPDs 
will be manually added into a
non-programmable excel sheet.
Taking medications that affect gastric pH
Non-programmable – Study team 
identified
1) Stats will create the list of 
patients who meet this IPD 
criteria based on a list of 
medications from Medical.
2) Among those, the true IPDs 
will be manually added into a 
non-programmable excel sheet.
Equipment
WMC patient education
Non-programmable – Monitor identified
WMC calibration
Non-programmable – Monitor identified
WMC assessment of expulsion
Non-programmable – Monitor identified
Other
Study treatment administration
Non-programmable – Monitor identified
Investigational 
Product
Patient took medication not 
fit for use
Patient received drug declared “Not Fit for Use”
Non-programmable – Monitor identified
Unblinding
Unjustified unblinding of patient treatment 
assignment
Non-programmable – Monitor identified
Abbreviations:  BMI = body mass index; CGRP = calcitonin gene-related peptide; GI = gastrointestinal; Hx = history; IBS = irritable bowel syndrome; 
IPD = important protocol deviation; mAb = monoclonal antibody; obst = obstruction; SAE = serious adverse event; Stats = Statistics; UC = ulcerative colitis; 
WMC = wireless motility capsule.


Leo Document ID = d175c1e3-062e-4757-85aa-db5774c7fac0
Approver: 
Approval Date & Time: 29-Sep-2020 17:14:06 GMT
Signature meaning: Approved
PPD